Long QT syndrome
ECG showing typical pattern of inherited Long QT syndrome (LQT1). A QT interval of >480ms is considered abnormally long.
Specialty	Cardiology
Symptoms	Fainting,hearing loss,seizures[1]
Complications	Sudden death[1]
Causes	Genetic, certain medications,low blood potassium,low blood calcium,heart failure[2]
Risk factors	Family history of sudden death[3]
Diagnostic method	Electrocardiogram (EKG), clinical findings, genetic testing[4][5]
Differential diagnosis	Brugada syndrome,arrhythmogenic right ventricular dysplasia[3]
Treatment	Avoiding strenuous exercise, getting sufficientpotassium,beta blockers,implantable cardiac defibrillator[6]
Frequency	≈ 1 in 7,000[6]
Deaths	≈3,500 a year (USA)[6]

Long QT syndrome (LQTS) is a condition in whichrepolarization of theheart after aheartbeat is affected.^[7] It results in an increased risk of anirregular heartbeat which can result infainting,drowning,seizures like activity, orsudden death.^[1] These episodes can be triggered by exercise or stress.^[6] Some rare forms of LQTS are associated with other symptoms includingdeafness andperiods of muscle weakness.^[1]

Long QT syndrome may be present at birth or develop later in life.^[1] Theinherited form may occur by itself or as part of largergenetic disorder.^[1] Onset later in life may result from certain medications,low blood potassium,low blood calcium, orheart failure.^[2] Medications that are implicated include certainantiarrhythmics,antibiotics, andantipsychotics.^[2] LQTS can be diagnosed using anelectrocardiogram (EKG) if acorrected QT interval of greater than 480–500 milliseconds is found, but clinical findings, other EKG features, andgenetic testing may confirm the diagnosis with shorter QT intervals.^[4][5]

Management may include avoiding strenuous exercise, getting sufficientpotassium in the diet, the use ofbeta blockers, or animplantable cardiac defibrillator.^[6] For people with LQTS who survivecardiac arrest and remain untreated, the risk of death within 15 years is greater than 50%.^[8][6] With proper treatment this decreases to less than 1% over 20 years.^[3]

Long QT syndrome is estimated to affect 1 in 7,000 people.^[6] Females are affected more often than males.^[6] Most people with the condition develop symptoms before they are 40 years old.^[6] It is a relatively common cause of sudden death along withBrugada syndrome andarrhythmogenic right ventricular dysplasia.^[3] In the United States it results in about 3,500 deaths a year.^[6] The condition was first clearly described in 1957.^[9]

Signs and symptoms

Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused byabnormal heart rhythms (arrhythmias), most commonly a form ofventricular tachycardia calledTorsades de pointes (TdP). If the arrhythmia reverts to anormal rhythm spontaneously the affected person may experience lightheadedness (known aspresyncope) orfaint which may be preceded by a fluttering sensation in the chest.^[6] If the arrhythmia continues, the affected person may experience acardiac arrest, which if untreated may lead to sudden death.^[10] Those with LQTS may also experienceseizure-like activity (non-epileptic seizure) as a result of reduced blood flow to the brain during an arrhythmia.^[11][12]Epilepsy is also associated with certain types of long QT syndrome.^[12]

The arrhythmias that lead to faints and sudden death are more likely to occur in specific circumstances, in part determined by whichgenetic 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).^[10][13]

Some rare forms of long QT syndrome affect other parts of the body, leading todeafness in theJervell and Lange-Nielsen form of the condition, andperiodic paralysis in theAndersen–Tawil (LQT7) form.^[4]

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.^[14] 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.^[15] 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.^[15]

In addition to a history of arrhythmias, the extent to which the QT is prolonged predicts risk. 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.^[16] Despite this, those with only subtle QT prolongation or concealed LQTS still have some risk of arrhythmias.^[10] Overall, every 10 ms increase in the corrected QT interval is associated with a 5% increase in arrhythmic risk.^[14]

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 experienceelectrolyte problems such as low blood levels of low 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.^[14] Arrhythmias occur more commonly indrug-induced LQTS if the medication in question has been rapidly givenintravenously, or if high concentrations of the drug are present in the person's blood.^[16] The risk of arrhythmias is also higher if the person receiving the drug hasheart failure, is takingdigitalis, or has recently been cardioverted fromatrial fibrillation.^[16] Other risk factors for developing torsades de pointes among those with LQTS include female sex, increasing age, pre-existingcardiovascular disease, and abnormalliver orkidney function.^[17]

Causes

There are several subtypes of long QT syndrome. These can be broadly split into those caused bygenetic 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).

Inherited

Inherited, or congenital long QT syndrome, is caused by genetic abnormalities. LQTS can arise from variants in several genes, leading in some cases to quite different features.^[18] The common thread linking these variants is that they affect one or moreion currents leading to prolongation of theventricular action potential, thus lengthening the QT interval.^[7] 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.^[19] The commonest of these, accounting for 99% of cases, isRomano–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.^[10] 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.^[20] Other rare forms include Anderson–Tawil syndrome (LQT7) with features including a prolonged QT interval, periodic paralysis, and abnormalities of the face and skeleton; andTimothy syndrome (LQT8) in which a prolonged QT interval is associated with abnormalities in the structure of the heart andautism spectrum disorder.^[4]

Romano–Ward syndrome

LQT1 is the most common subtype of Romano–Ward syndrome, responsible for 30 to 35% of all cases.^[21] The gene responsible,KCNQ1, has been isolated tochromosome 11p15.5 and encodes the alpha subunit of theKvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier currentI_Ks responsible for the repolarisation phase of thecardiac action potential.^[21] Variants inKCNQ1 that decreaseI_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) leads to the more severe Jervell and Lange–Nielsen syndrome.^[21] Conversely, variants in KCNQ1 that increaseI_Ks lead to more rapid repolarisation and theshort QT syndrome.^[22]

The LQT2 subtype is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases.^[21] It is caused by variants in theKCNH2 gene (also known ashERG) on chromosome 7 which encodes the potassium channel that carries the rapid inward rectifier currentI_Kr.^[21] This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the QT interval.^[21]

The LQT3 subtype of Romano–Ward syndrome is caused by variants in theSCN5A gene located on chromosome 3p21–24.SCN5A encodes the alpha subunit of the cardiac sodium channel, Na_V1.5, responsible for the sodium currentI_Na which depolarises cardiac cells at the start of the action potential.^[21] 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.^[21] While some variants inSCN5A cause LQT3, other variants can cause quite different conditions. Variants causing a reduction in the early peak current can causeBrugada syndrome and cardiac conduction disease, while other variants have been associated withdilated cardiomyopathy. Some variants which affect both the early and late sodium current can causeoverlap syndromes which combine aspects of both LQT3 and Brugada syndrome.^[10]

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

LQT5 is caused by variants in theKCNE1 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 currentI_Ks which is decreased in LQTS.^[21] LQT6 is caused by variants in theKCNE2 gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium currentI_Kr.^[21] Variants that decrease this current have been associated with prolongation of the QT interval.^[20] 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.^[19] Some therefore dispute whether variants inKCNE2 are sufficient to cause Romano-Ward syndrome by themselves.^[19]

LQT9 is caused by variants in the membrane structural protein,caveolin-3.^[21] Caveolins form specific membrane domains calledcaveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase the late sustained sodium current, which impairs cellularrepolarization.^[21]

LQT10 is an extremely rare subtype, caused by variants in theSCN4B 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.^[21] LQT13 is caused by variants inGIRK4, a protein involved in the parasympathetic modulation of the heart.^[21] 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, andCALM3 respectively).^[21] 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 byKCNQ1 and thereby influencing potassium currents.^[21] The precise mechanisms by which means these genetic variants prolong the QT interval remain uncertain.^[21]

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 certain variant in theKCNE1 orKCNQ1 genes. The same genetic variants lead to the LQT1 and LQT5 forms of Romano-Ward syndrome if only a single copy of the variant is inherited.^[10] JLNS is generally associated with a higher risk of arrhythmias than most other forms of LQTS.^[4]

Andersen–Tawil syndrome (LQT7)

LQT7, also known asAndersen–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 andclinodactyly). The condition is inherited in an autosomal-dominant manner and is frequently associated with mutations in theKCNJ2 gene which encodes the potassium channel protein K_ir2.1.^[23]

Timothy syndrome (LQT8)

LQT8, also known asTimothy syndrome combines a prolonged QT interval with fused fingers or toes (syndactyly). Abnormalities of the structure of the heart are commonly seen includingventricular septal defect,tetralogy of Fallot, andhypertrophic cardiomyopathy.^[24][25] 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 ofautism spectrum disorder. Timothy syndrome is caused by variants in the calcium channel Cav1.2 encoded by the geneCACNA1c.^[26]

Table of associated genes

The following is a list of genes associated with LQTS:

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 byantiarrhythmic drugs such asamiodarone andsotalol, antibiotics such aserythromycin, orantihistamines such asterfenadine.^[17] Other drugs which prolong the QT interval include someantipsychotics such ashaloperidol andziprasidone, and theantidepressantcitalopram.^[27][16] Lists of medications associated with prolongation of the QT interval such as theCredibleMeds database can be found online.^[28]

Other causes of acquired LQTS include abnormally low levels of potassium (hypokalaemia) or magnesium (hypomagnesaemia) within the blood. This is 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).^[29]

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 causingsudden cardiac death. The malnutrition and associated changes in salt balance develop over a prolonged period of time, 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 ofrefeeding syndrome.^[30]

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.^[29]

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 thecardiac action potential – the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat.^[10] Heart cells when relaxed normally have fewer positively chargedions on the inner side of theircell membrane than on the outer side, referred to as the membrane beingpolarised. When heart cellscontract, positively charged ions such as sodium and calcium enter the cell, equalising or reversing this polarity, ordepolarising the cell. After a contraction has taken place, the cell restores its polarity (orrepolarises) 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.^[10]

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 ofafterdepolarisations. 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 sodiumchannels that would normally switch off until the next heartbeat is due.^[31] Under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell.^[31] The early afterdepolarisations triggering arrhythmias in long QT syndrome tend to arise from thePurkinje fibres of the cardiac conduction system.^[32] Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell.^[31]

Some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long QT syndrome.^[32] This form of afterdepolarisation originates from the spontaneous release of calcium from the intracellular calcium store known as thesarcoplasmic reticulum, forcing calcium out of cell through thesodium calcium exchanger in exchange for sodium, generating a net inward current.^[31]

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.^[32] 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 theheart muscle with longer action potentials in some layers than others.^[32] 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 meanderingspiral wave.^[32]

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.^[20] Conversely, given the normal distribution of QT intervals, a proportion of healthy people will have a longer QT interval than any arbitrary cutoff.^[20] 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 theQT 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.^[20] 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 99thcentiles of normal values.^[20]

The major subtypes of inherited LQTS are associated with specific ECG features. LQT1 is typically associated with broad-basedT-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.^[20]

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 designed to unmask a prolonged QT may be helpful. In addition to its effect on the QT interval at rest, LQTS affects 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.^[34] These investigations are most useful for identifying the group of those with congenital LQTS type 1 (LQT1) who have a normal QT interval at rest. In these people, exercise or adrenaline infusion can lead to paradoxical prolongation of the QT interval, revealing the underlying condition.^[20]

Guideline cutoffs

International consensus guidelines differ on the degree of QT prolongation required to diagnose LQTS. TheEuropean 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] TheHeart 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 inpublic access online databases.^[35] In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination.

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 ofbeta receptor blocking agents, which decreases the risk of stress-induced arrhythmias. Beta blockers are an effective treatment for LQTS caused by LQT1 and LQT2.^[7]

Genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blocker therapy. To be specific, the presence of QTc >500 ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients, primary prevention with use ofimplantable cardioverter-defibrillators can be considered.^[7]

• Potassium supplementation: If the potassium content in the blood rises, the action potential shortens, so increasing potassium concentration could minimize the occurrence of arrhythmias. It should work best in LQT2, since the hERG channel is especially sensitive to potassium concentration, but the use is experimental and not evidence-based.
• Sodium channel blocking drugs such asmexiletine have been used to prevent arrhythmias in long QT syndrome.^[36] While the most compelling indication is for those whose long QT syndrome is caused by defective sodium channels producing a sustained late current (LQT3), mexiletine also shortens the QT interval in other forms of long QT syndrome including LQT1, LQT2 and LQT8.^[36] 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 asranolazine may be more effective, although evidence that this is the case in practice is limited.^[36]
• Amputation of thecervical sympathetic chain (leftstellectomy). 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.

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.

With better knowledge of the genetics underlying LQTS, more precise treatments hopefully will become available.^[37]

Outcomes

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%.^[8] 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.^[20][38]

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 inLeipzig 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.^[39] 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 byAnton Jervell andFred Lange-Nielsen, working inTønsberg,Norway.^[40] Italian pediatrician Cesarino Romano, in 1963,^[41] and Irish pediatrician Owen Conor Ward, in 1964,^[42] 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 numerouspedigrees to be evaluated in a comprehensive manner. This helped in detecting many of the numerous genes involved.^[43]

References

Notes

• Goldman, Lee (2011).Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 1196.ISBN 978-1437727883.{{cite book}}:Invalid|ref=harv (help)

External links

• CredibleMeds.orgArchived 2021-07-15 at theWayback Machine, contains a list of drugs that prolong the QT interval

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• Cardiac arrhythmia
• Channelopathies
• Syndromes affecting the heart
• Cytoskeletal defects
• Cardiogenetic disorders
• Single-nucleotide polymorphism associated disease
• RTT