View source for Long QT syndrome

{{Infobox medical condition (new)
| name          = Long QT syndrome
| synonyms      = 
| image         = Long_QT_syndrome_type_1.jpg
| caption       = ECG showing typical pattern of inherited Long QT syndrome (LQT1). A QT interval of >480 ms is considered abnormally long.
| pronounce     = 
| field         = [[Cardiology]]
| symptoms      = [[syncope (medicine)|Fainting]], [[hearing loss]], [[seizures]]<ref name=GARD2017/>
| complications = [[Sudden cardiac death|Sudden death]]<ref name=GARD2017/>
| onset         = 
| duration      = 
| types         = 
| causes        = [[Genetics|Genetic]], certain medications, [[hypokalemia|low blood potassium]], [[hypocalcemia|low blood calcium]], [[heart failure]]<ref name=Mor2008/>
| risks         = Family history of sudden death<ref name=Fer2016/>
| diagnosis     = [[Electrocardiogram]] (EKG), clinical findings, genetic testing <ref name="ESC 2015" /><ref name="HRS guidelines" />
| differential  = [[Brugada syndrome]], [[arrhythmogenic right ventricular dysplasia]]<ref name=Fer2016/>
| prevention    = 
| treatment     = Avoiding strenuous exercise, getting sufficient [[potassium]], [[beta blockers]], [[implantable cardiac defibrillator]]<ref name=NIH2017/>
| medication    = 
| prognosis     = 
| frequency     = ≈ 1 in 7,000<ref name=NIH2017/>
| deaths        = ≈3,500 a year (U.S.)<ref name=NIH2017/>
| alt           = 
}}
<!-- Definition and symptoms -->

'''Long QT syndrome''' ('''LQTS''') is a condition affecting [[repolarization]] (relaxing) of the [[heart]] after a [[Cardiac cycle|heartbeat]], giving rise to an abnormally lengthy [[QT interval]].<ref name="Levine2008">{{cite journal | vauthors = Levine E, Rosero SZ, Budzikowski AS, Moss AJ, Zareba W, Daubert JP | s2cid = 4237579 | title = Congenital long QT syndrome: considerations for primary care physicians | journal = Cleveland Clinic Journal of Medicine | volume = 75 | issue = 8 | pages = 591–600 | date = August 2008 | pmid = 18756841 | doi = 10.3949/ccjm.75.8.591 | doi-broken-date = 12 July 2025 | author-link4 = Arthur J. Moss }}</ref> It results in an increased risk of an [[cardiac arrhythmia|irregular heartbeat]] which can result in [[Syncope (medicine)|fainting]], [[drowning]], [[seizures]], or [[sudden cardiac death|sudden death]].<ref name=GARD2017>{{cite web|title=Long QT syndrome|url=https://rarediseases.info.nih.gov/diseases/6922/long-qt-syndrome|website=Genetic and Rare Diseases Information Center (GARD) – an NCATS Program|access-date=14 December 2017|language=en|date=2017|archive-date=14 December 2017|archive-url=https://web.archive.org/web/20171214072202/https://rarediseases.info.nih.gov/diseases/6922/long-qt-syndrome}}</ref> These episodes can be triggered by exercise or stress.<ref name=NIH2017>{{cite web|title=Long QT Syndrome|url=https://www.nhlbi.nih.gov/health/long-qt-syndrome|website=NHLBI, NIH|access-date=14 December 2017|language=en}}</ref> Some rare forms of LQTS are associated with other symptoms and signs, including [[Hearing loss|deafness]] and [[Periodic paralysis|periods of muscle weakness]].<ref name=GARD2017/>

<!-- Cause and diagnosis -->
Long QT syndrome may be present at birth or develop later in life.<ref name=GARD2017/> The [[heredity|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, [[hypokalemia|low blood potassium]], [[hypocalcemia|low blood calcium]], or [[heart failure]].<ref name=Mor2008/> Medications that are implicated include certain [[antiarrhythmic]]s, [[antibiotics]], and [[antipsychotics]].<ref name=Mor2008>{{cite journal | vauthors = Morita H, Wu J, Zipes DP | s2cid = 41181673 | title = The QT syndromes: long and short | journal = Lancet | volume = 372 | issue = 9640 | pages = 750–63 | date = August 2008 | pmid = 18761222 | doi = 10.1016/S0140-6736(08)61307-0 }}</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>{{Cite journal |last1=Afzal |first1=Muhammad Adil |last2=Khalid |first2=Noman |last3=Abdullah |first3=Muhammad |last4=ul-Haiy |first4=Ata |last5=Michael |first5=Patrick |title=Hydroxyzine-Induced Torsade De Pointes: A Case Report and a Literature Review |journal=Cureus |date=2023 |volume=15 |issue=7 |article-number=e41588 |doi=10.7759/cureus.41588 |doi-access=free |issn=2168-8184 |pmid=37559846|pmc=10407684 }}</ref>

<!-- Treatment -->
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>{{cite journal | vauthors = Ackerman MJ, Priori SG, Dubin AM, Kowey P, Linker NJ, Slotwiner D, Triedman J, Van Hare GF, Gold MR | display-authors = 6 | title = Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: Are all beta-blockers equivalent? | journal = Heart Rhythm | volume = 14 | issue = 1 | pages = e41–e44 | date = January 2017 | pmid = 27659101 | doi = 10.1016/j.hrthm.2016.09.012 | quote = Among patients who have experienced a LQTS-triggered cardiac event (arrhythmic syncope, arrhythmic syncope followed by seizures, or aborted cardiac arrest), the untreated natural history is grim, with >50% mortality at 15 years. | doi-access = free }} {{open access}}</ref><ref name=NIH2017/><!-- Quote = More than half of the people who have untreated, inherited types of LQTS die within 10 years --> With proper treatment, this decreases to less than 1% over 20 years.<ref name=Fer2016>{{cite book|last1=Ferri|first1=Fred F. | name-list-style = vanc |title=Ferri's Clinical Advisor 2017 E-Book: 5 Books in 1|date=2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44838-3|page=736|url=https://books.google.com/books?id=rRhCDAAAQBAJ&pg=PA736|language=en}}</ref>

<!-- Epidemiology -->
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>{{cite book |last1=Vincent |first1=Jean-Louis |last2=Abraham |first2=Edward |last3=Kochanek |first3=Patrick |last4=Moore |first4=Frederick A. |last5=Fink |first5=Mitchell P. | name-list-style = vanc |title=Textbook of Critical Care E-Book |date=2011 |publisher=Elsevier Health Sciences |isbn=978-1-4377-1568-2 |page=578 |url=https://books.google.com/books?id=uAl68tCzm5IC&pg=PA578 }}</ref>
{{TOC limit}}

== Signs and symptoms ==
[[File:De-Acquired longQT (CardioNetworks ECGpedia).jpg|upright=1.6|thumb|Acquired long QT syndrome]]
Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused by [[Arrhythmia|abnormal heart rhythms]] (arrhythmias), most commonly a form of [[ventricular tachycardia]] called [[Torsades de pointes]] (TdP). If the arrhythmia reverts to a [[Sinus rhythm|normal rhythm]] spontaneously, the affected person may experience lightheadedness (known as [[presyncope]]) or [[Syncope (medicine)|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 seizure]]s as a result of reduced blood flow to the brain during an arrhythmia.<ref>{{cite book|url=https://books.google.com/books?id=VbjFQiz8aR0C&pg=PA1677|title=Oski's Pediatrics: Principles & Practice|last1=McMillan|first1=Julia A.|last2=Feigin|first2=Ralph D.|last3=DeAngelis|first3=Catherine|last4=Jones|first4=M. Douglas | name-list-style = vanc |date=2006|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-3894-1|page=1677|language=en}}</ref><ref name=Mad2017>{{cite journal | vauthors = Madan N, Carvalho KS | title = Neurological Complications of Cardiac Disease | journal = Seminars in Pediatric Neurology | volume = 24 | issue = 1 | pages = 3–13 | date = February 2017 | pmid = 28779863 | doi = 10.1016/j.spen.2017.01.001 | quote = Syncope can lead to convulsions and can easily be confused with epileptic seizures. }}</ref> [[Epilepsy]] is also associated with certain types of long QT syndrome.<ref name=Mad2017/><!-- Quote =  They demonstrated that a seizure phenotype was far more common in patients with LQT2 compared to either background rates or to patients with LQT1. -->

The arrhythmias that lead to faints and sudden death are more likely to occur in specific circumstances, in part determined by which [[Mutation|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>{{cite journal | vauthors = Nakajima T, Kaneko Y, Kurabayashi M | title = Unveiling specific triggers and precipitating factors for fatal cardiac events in inherited arrhythmia syndromes | journal = Circulation Journal | volume = 79 | issue = 6 | pages = 1185–92 | date = 2015 | pmid = 25925977 | doi = 10.1253/circj.CJ-15-0322 | doi-access = free }}</ref>

Some rare forms of long QT syndrome affect other parts of the body, leading to [[Hearing loss|deafness]] in the [[Jervell and Lange-Nielsen syndrome|Jervell and Lange-Nielsen]] form of the condition, and [[periodic paralysis]] in the [[Andersen–Tawil syndrome|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">{{cite journal | vauthors = Trinkley KE, Page RL, Lien H, Yamanouye K, Tisdale JE | s2cid = 206967580 | title = QT interval prolongation and the risk of torsades de pointes: essentials for clinicians | journal = Current Medical Research and Opinion | volume = 29 | issue = 12 | pages = 1719–26 | date = December 2013 | pmid = 24020938 | doi = 10.1185/03007995.2013.840568 }}</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">{{cite journal | vauthors = Barsheshet A, Dotsenko O, Goldenberg I | title = Genotype-specific risk stratification and management of patients with long QT syndrome | journal = Annals of Noninvasive Electrocardiology | volume = 18 | issue = 6 | pages = 499–509 | date = November 2013 | pmid = 24206565 | pmc = 6932574 | doi = 10.1111/anec.12117 }}</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">{{Cite journal |last1=Priori |first1=Silvia G. |last2=Schwartz |first2=Peter J. |last3=Napolitano |first3=Carlo |last4=Bloise |first4=Raffaella |last5=Ronchetti |first5=Elena |last6=Grillo |first6=Massimiliano |last7=Vicentini |first7=Alessandro |last8=Spazzolini |first8=Carla |last9=Nastoli |first9=Janni |last10=Bottelli |first10=Georgia |last11=Folli |first11=Roberta |date=2003-05-08 |title=Risk Stratification in the Long-QT Syndrome |journal=New England Journal of Medicine |language=en |volume=348 |issue=19 |pages=1866–1874 |doi=10.1056/NEJMoa022147 |pmid=12736279 |issn=0028-4793|doi-access=free }}</ref><ref name=":7">{{Cite journal |last1=Mazzanti |first1=Andrea |last2=Maragna |first2=Riccardo |last3=Vacanti |first3=Gaetano |last4=Monteforte |first4=Nicola |last5=Bloise |first5=Raffaella |last6=Marino |first6=Maira |last7=Braghieri |first7=Lorenzo |last8=Gambelli |first8=Patrick |last9=Memmi |first9=Mirella |last10=Pagan |first10=Eleonora |last11=Morini |first11=Massimo |date=April 2018 |title=Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome |journal=Journal of the American College of Cardiology |language=en |volume=71 |issue=15 |pages=1663–1671 |doi=10.1016/j.jacc.2018.01.078|pmid=29650123 |hdl=20.500.12105/10498 |doi-access=free |hdl-access=free }}</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">{{cite journal | vauthors = Roden DM | s2cid = 15251057 | title = Drug-induced prolongation of the QT interval | journal = The New England Journal of Medicine | volume = 350 | issue = 10 | pages = 1013–22 | date = March 2004 | pmid = 14999113 | doi = 10.1056/NEJMra032426 }}</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 imbalance|electrolyte problems]] such as low blood levels of potassium ([[Hypokalemia|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 [[Intravenous therapy|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 [[Digoxin|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 failure|liver]] or [[Renal function|kidney function]].<ref name=":1">{{cite journal|last1=Thomson|first1=Clare|last2=Wright|first2=Paul|name-list-style=vanc|title=Long QT syndrome|journal=The Pharmaceutical Journal|date=2014-10-15|volume=293|issue=7833|url=http://www.pharmaceutical-journal.com/topics/cpd/long-qt-syndrome/20066791.cpdarticle|access-date=18 October 2014|archive-date=2014-10-20|archive-url=https://web.archive.org/web/20141020023426/http://www.pharmaceutical-journal.com/topics/cpd/long-qt-syndrome/20066791.cpdarticle}}</ref>

==Causes==
There are several subtypes of long QT syndrome. These can be broadly split into those caused by [[Mutation|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).{{citation needed|date=February 2021}}

===Inherited===
[[File:PMC2322962 Zhang 2008 Comparison of normal, Romano-Ward and Jervell-Lange-Nielsen ECGs in same family.jpg|thumb|Electrocardiograms from a single family showing unaffected family member (top), [[Romano–Ward syndrome|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">{{cite journal | vauthors = Hedley PL, Jørgensen P, Schlamowitz S, Wangari R, Moolman-Smook J, Brink PA, Kanters JK, Corfield VA, Christiansen M | display-authors = 6 | title = The genetic basis of long QT and short QT syndromes: a mutation update | journal = Human Mutation | volume = 30 | issue = 11 | pages = 1486–511 | date = November 2009 | pmid = 19862833 | doi = 10.1002/humu.21106 | s2cid = 19122696 | doi-access = free }}</ref>  The common thread linking these variants is that they affect one or more [[Ion channel|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">{{cite book | vauthors = Tester DJ, Schwartz PJ, Ackerman MJ | date = 2013 | chapter = Congenital Long QT Syndrome | veditors = Gussak I, Antzelevitch C | title = Electrical Diseases of the Heart | publisher = Springer | location = London | pages = 439–468 | doi = 10.1007/978-1-4471-4881-4_27 | isbn = 978-1-4471-4881-4 }}</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|autism spectrum disorder]].<ref name="ESC 2015">{{cite journal | vauthors = Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ | display-authors = 6 | title = 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC) | journal = Europace | volume = 17 | issue = 11 | pages = 1601–87 | date = November 2015 | pmid = 26318695 | doi = 10.1093/europace/euv319 | doi-access = free | hdl = 11577/3455356 | hdl-access = free }}</ref>

==== Romano–Ward syndrome ====
{{main|Romano–Ward syndrome}}
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 11]]p15.5 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''<sub>Ks</sub> responsible for the repolarisation phase of the [[cardiac action potential]].<ref name="Bohnen 2017" /> Variants in ''KCNQ1'' that decrease ''I''<sub>Ks</sub> (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''<sub>Ks</sub> lead to more rapid repolarisation and the [[short QT syndrome]].<ref>{{cite journal | vauthors = Bjerregaard P | title = Diagnosis and management of short QT syndrome | journal = Heart Rhythm | volume = 15 | issue = 8 | pages = 1261–1267 | date = August 2018 | pmid = 29501667 | doi = 10.1016/j.hrthm.2018.02.034 | s2cid = 4519580 }}</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 ''[[hERG|KCNH2]]'' gene (also known as ''hERG'') on chromosome 7 which encodes the potassium channel that carries the rapid inward rectifier current ''I''<sub>Kr</sub>.<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<sub>V</sub>1.5, responsible for the sodium current ''I''<sub>Na</sub> 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''<sub>Ks</sub> which is decreased in LQTS.<ref name="Bohnen 2017">{{cite journal | vauthors = Bohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, Kass RS | title = Molecular Pathophysiology of Congenital Long QT Syndrome | journal = Physiological Reviews | volume = 97 | issue = 1 | pages = 89–134 | date = January 2017 | pmid = 27807201 | pmc = 5539372 | doi = 10.1152/physrev.00008.2016 }}</ref>  LQT6 is caused by variants in the ''KCNE2'' gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium current ''I''<sub>Kr</sub>.<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]]<nowiki>-3</nowiki>.<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<sub>V</sub>β4) 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">{{cite journal | vauthors = Wang F, Liu J, Hong L, Liang B, Graff C, Yang Y, Christiansen M, Olesen SP, Zhang L, Kanters JK | title = The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R) | journal = Heart Rhythm | volume = 10 | issue = 10 | pages = 1500–6 | date = 2013 | pmid = 23872692 | doi = 10.1016/j.hrthm.2013.07.022 }}</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 ====
{{main|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) ====
{{main|Andersen–Tawil 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 ([[Micrognathism|micrognathia]]), low set ears, and fused or abnormally angled fingers and toes ([[syndactyly]] and [[clinodactyly]]).<ref>{{Cite journal |last1=Mazzanti |first1=Andrea |last2=Guz |first2=Dmitri |last3=Trancuccio |first3=Alessandro |last4=Pagan |first4=Eleonora |last5=Kukavica |first5=Deni |last6=Chargeishvili |first6=Tekla |last7=Olivetti |first7=Natalia |last8=Biernacka |first8=Elżbieta Katarzyna |last9=Sacilotto |first9=Luciana |last10=Sarquella-Brugada |first10=Georgia |last11=Campuzano |first11=Oscar |date=April 2020 |title=Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1 |journal=Journal of the American College of Cardiology |language=en |volume=75 |issue=15 |pages=1772–1784 |doi=10.1016/j.jacc.2020.02.033|pmid=32299589 |s2cid=215803995 |doi-access=free |hdl=10668/15382 |hdl-access=free }}</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<sub>ir</sub>2.1.<ref>{{cite journal | vauthors = Nguyen HL, Pieper GH, Wilders R | title = Andersen-Tawil syndrome: clinical and molecular aspects | journal = International Journal of Cardiology | volume = 170 | issue = 1 | pages = 1–16 | date = December 2013 | pmid = 24383070 | doi = 10.1016/j.ijcard.2013.10.010 }}</ref>

==== Timothy syndrome (LQT8) ====
{{main|Timothy syndrome}}

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>{{Cite book |last1=Napolitano |first1=Carlo |url=https://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews |last2=Timothy |first2=Katherine W. |last3=Bloise |first3=Raffaella |last4=Priori |first4=Silvia G. |date=Feb 11, 2021 |publisher=University of Washington, Seattle |editor-last=Adam |editor-first=Margaret P. |location=Seattle (WA) |chapter=CACNA1C-Related Disorders |pmid=20301577 |orig-date=1993 |editor-last2=Feldman |editor-first2=Jerry |editor-last3=Mirzaa |editor-first3=Ghayda |editor-last4=Pagon |editor-first4=Roberta A. |editor-last5=Wallace |editor-first5=Stephanie E. |editor-last6=Bean |editor-first6=Laura J.H. |editor-last7=Gripp |editor-first7=Karen W. |editor-last8=Amemiya |editor-first8=Anne |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK1403/}}</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|autism spectrum disorder]].  Timothy syndrome is caused by variants in the calcium channel Cav1.2 encoded by the gene ''CACNA1c''.<ref>{{Cite book |last1=Tristani-Firouzi |first1=Martin |title=Electrical Diseases of the Heart |last2=Etheridge |first2=Susan P. |date=2013 |publisher=Springer London |isbn=978-1-4471-4880-7 |editor-last=Gussak |editor-first=Ihor |pages=561–567 |chapter=Andersen–Tawil and Timothy Syndromes |doi=10.1007/978-1-4471-4881-4_32 |editor-last2=Antzelevitch |editor-first2=Charles |name-list-style=vanc}}</ref>

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

{| class="wikitable"
! Type
! OMIM
! Gene
! Notes
|-
|LQT1
|{{OMIM|192500||none}}
|[[KvLQT1|''KCNQ1'']]
|Encodes the α-subunit of the slow delayed rectifier potassium channel K<sub>V</sub>7.1 carrying the potassium current ''I''<sub>Ks</sub>.<ref name="Giudicessi 2018">{{cite journal | vauthors = Giudicessi JR, Wilde AA, Ackerman MJ | title = The genetic architecture of long QT syndrome: A critical reappraisal | journal = Trends in Cardiovascular Medicine | volume = 28 | issue = 7 | pages = 453–464 | date = October 2018 | pmid = 29661707 | pmc = 6590899 | doi = 10.1016/j.tcm.2018.03.003 }}</ref>
|-
|LQT2
|{{OMIM|152427||none}}
|[[HERG|''KCNH2'']]
|Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel K<sub>V</sub>11.1 carrying the potassium current ''I''<sub>Kr</sub>.<ref name="Giudicessi 2018" />
|-
|LQT3
|{{OMIM|603830||none}}
|''[[SCN5A]]''
|Encodes the α-subunit of the cardiac sodium channel Na<sub>V</sub>1.5 carrying the sodium current ''I''<sub>Na</sub>.<ref name="Giudicessi 2018" />
|-
|LQT4
|{{OMIM|600919||none}}
|[[Ankyrin B|''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
|{{OMIM|176261||none}}
|''[[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
|{{OMIM|603796||none}}
|''[[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
|{{OMIM|170390||none}}
|''[[KCNJ2]]''
|Encodes inward rectifying potassium current K<sub>ir</sub>2.1 carrying the potassium current ''I''<sub>K1</sub>. Causes [[Andersen–Tawil syndrome]].<ref name="Giudicessi 2018" />
|-
|LQT8
|{{OMIM|601005||none}}
|''[[CACNA1c]]''
|Encodes the α-subunit Ca<sub>V</sub>1.2 of the [[calcium channel]] Cav1.2 carrying the calcium current ''I''<sub>Ca(L).</sub> Causes [[Timothy's syndrome|Timothy syndrome]].<ref name="Giudicessi 2018" />
|-
|LQT9
|{{OMIM|611818||none}}
|[[Caveolin 3|''CAV3'']]
|Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current ''I''<sub>Na</sub>.<ref name="Giudicessi 2018" />
|-
|LQT10
|{{OMIM|611819||none}}
|''[[SCN4B]]''
|Encodes the β4-subunit of the cardiac sodium channel.<ref name="Giudicessi 2018" />
|-
|LQT11
|{{OMIM|611820||none}}
|''[[AKAP9]]''
|Encodes A-kinase associated protein which interacts with K<sub>V</sub>7.1.<ref name="Giudicessi 2018" />
|-
|LQT12
|{{OMIM|601017||none}}
|''[[SNTA1]]''
|Encodes syntrophin-α1.  Mutations in this gene may increase the late sodium current ''I''<sub>Na</sub>.<ref name="Giudicessi 2018" />
|-
|LQT13
|{{OMIM|600734||none}}
|''[[KCNJ5]]''
|Also known as ''[[GIRK4]],'' encodes G protein-sensitive inwardly rectifying potassium channels (K<sub>ir</sub>3.4) which carry the potassium current ''I''<sub>K(ACh)</sub>.<ref name="Giudicessi 2018" /><ref name="Wang 2013" />
|-
|LQT14
|{{OMIM|616247||none}}
|''[[CALM1]]''
|Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ''I''<sub>Ca(L)</sub>.<ref name="Giudicessi 2018" />
|-
|LQT15
|{{OMIM|616249||none}}
|''[[CALM2]]''
|Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current  ''I''<sub>Ca(L)</sub>.<ref name="Giudicessi 2018" />
|-
|LQT16
|{{OMIM|114183||none}}
|''[[CALM3]]''
|Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ''I''<sub>Ca(L)</sub>.<ref name="Giudicessi 2018" />
|}

=== Acquired ===
{{main|Drug-induced QT prolongation}}

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 agent|antiarrhythmic]] drugs such as [[amiodarone]] and [[sotalol]], antibiotics such as [[erythromycin]], or [[antihistamine]]s such as [[terfenadine]].<ref name=":1" /> Other drugs which prolong the QT interval include some [[antipsychotic]]s such as [[haloperidol]] and [[ziprasidone]],  and the [[antidepressant]] [[citalopram]].<ref>{{cite journal | vauthors = Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC | title = QTc prolongation, torsades de pointes, and psychotropic medications | journal = Psychosomatics | volume = 54 | issue = 1 | pages = 1–13 | date = January 2013 | pmid = 23295003 | doi = 10.1016/j.psym.2012.11.001 | doi-access =  }}</ref><ref name="Roden" /> Lists of medications associated with prolongation of the QT interval, such as the [[CredibleMeds]] database, can be found online.<ref>{{cite journal | vauthors = Woosley RL, Black K, Heise CW, Romero K | title = CredibleMeds.org: What does it offer? | journal = Trends in Cardiovascular Medicine | volume = 28 | issue = 2 | pages = 94–99 | date = February 2018 | pmid = 28801207 | doi = 10.1016/j.tcm.2017.07.010 | url = https://repository.arizona.edu/bitstream/10150/627826/1/CM_What_does_it_offer.pdf | hdl = 10150/627826 | hdl-access = free }}</ref>

Other causes of acquired LQTS include abnormally low levels of potassium ([[Hypokalemia|hypokalaemia]]) or magnesium ([[Magnesium deficiency|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">{{cite journal | vauthors = El-Sherif N, Turitto G, Boutjdir M | title = Acquired long QT syndrome and torsade de pointes | journal = Pacing and Clinical Electrophysiology | volume = 41 | issue = 4 | pages = 414–421 | date = April 2018 | pmid = 29405316 | doi = 10.1111/pace.13296 | s2cid = 46795997 }}</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">{{cite journal | vauthors = Jáuregui-Garrido B, Jáuregui-Lobera I | title = Sudden death in eating disorders | journal = Vascular Health and Risk Management | volume = 8 | pages = 91–8 | date = February 2012 | pmid = 22393299 | pmc = 3292410 | doi = 10.2147/VHRM.S28652 | doi-access = free }}</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 ==
[[File:Mechanisms of arrhythmia.jpg|thumb|upright=1.4|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 [[Ion trap|ions]] on the inner side of their [[cell membrane]] than on the outer side, referred to as the membrane being ''polarised''. When heart cells [[Muscle contraction|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 [[Afterdepolarization|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 [[Ion channel|channels]] that would normally switch off until the next heartbeat is due.<ref name="Wit 2017">{{cite journal | vauthors = Wit AL | title = Afterdepolarizations and triggered activity as a mechanism for clinical arrhythmias | journal = Pacing and Clinical Electrophysiology | volume = 41 | issue = 8 | pages = 883–896 | date = June 2018 | pmid = 29920724 | doi = 10.1111/pace.13419 | s2cid = 49310809 }}</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 fibers|Purkinje fibres]] of the cardiac conduction system.<ref name="Sherif 2019">{{cite journal | vauthors = El-Sherif N, Turitto G, Boutjdir M | title = Acquired Long QT Syndrome and Electrophysiology of Torsade de Pointes | journal = Arrhythmia & Electrophysiology Review | volume = 8 | issue = 2 | pages = 122–130 | date = May 2019 | pmid = 31114687 | pmc = 6528034 | doi = 10.15420/aer.2019.8.3 | doi-broken-date = 1 July 2025 }}</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|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 [[Cardiac muscle|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 ==
[[File:PMC4040880 Postema 2014 QT interval measurement.jpg|thumb|Measurement of the [[QT interval]] with normal and prolonged QT intervals]]
[[File:QT distribution.png|thumb|Range of QT intervals expected in healthy males, healthy females, and those with long QT syndrome|alt=|left]]
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 ===
[[File:Long QT subtypes.jpg|thumb|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 [[Percentile|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 wave|T-waves]], whereas the T-waves in LQT2 are [[Notching in electrocardiography|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 ===
[[File:PMC4608198 Shashank 2015 Long QT2 with T-wave alternans.jpg|thumb|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.
{| class="wikitable"
|+ Schwartz score to aid diagnosis of inherited long QT syndrome.<ref name="pmid8339437">{{cite journal | vauthors = Schwartz PJ, Moss AJ, Vincent GM, Crampton RS | title = Diagnostic criteria for the long QT syndrome. An update | journal = Circulation | volume = 88 | issue = 2 | pages = 782–4 | date = August 1993 | pmid = 8339437 | doi = 10.1161/01.CIR.88.2.782 | doi-access = free }}</ref>
|-
| rowspan="3" |Corrected QT interval (QTc)
|≥ 480 ms
|3 points
| rowspan="3" |QTc defined according to [[QT interval|Bazett's correction]]
|-
|460–470 ms
|2 points
|-
|450 ms and male gender
|1 point
|-
|[[Torsades de pointes]]
|
|2 points
| rowspan="4" |
|-
|[[T wave alternans|T-wave alternans]]
|
|1 point
|-
|[[Notching in electrocardiography|Notched]] T-waves in at least 3 leads
|
|1 point
|-
|Low heart rate for age (children)
|
|0.5 points
|-
| rowspan="2" |Syncope
|with stress
|2 points
| rowspan="2" |Cannot receive points both for syncope and Torsades
|-
|without stress
|1 point
|-
|Congenital deafness
|
|0.5 points
|
|-
| rowspan="2" |Family history
|Other family member with confirmed LQTS
|1 point
| rowspan="2" |Same family member cannot be counted for LQTS and sudden death
|-
|Sudden cardiac death in an immediate family member aged <30
|0.5 point
|-
| colspan="4" |'''Score: 0–1: low probability of LQTS; 2–3: intermediate probability of LQTS; ≥&nbsp;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>{{cite journal | vauthors = Obeyesekere MN, Klein GJ, Modi S, Leong-Sit P, Gula LJ, Yee R, Skanes AC, Krahn AD | display-authors = 6 | title = How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia | journal = Circulation: Arrhythmia and Electrophysiology | volume = 4 | issue = 6 | pages = 958–64 | date = December 2011 | pmid = 22203660 | doi = 10.1161/CIRCEP.111.965947 | doi-access = free }}</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">{{cite journal | vauthors = Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C, Ackerman M, Belhassen B, Estes NA, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC | display-authors = 6 | title = Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes | journal = Europace | volume = 15 | issue = 10 | pages = 1389–406 | date = October 2013 | pmid = 23994779 | doi = 10.1093/europace/eut272 }}</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 [[CredibleMeds|public access online databases]].<ref>{{cite web |url=http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm |title=QT Drug List by Risk Groups |publisher=Arizona Center for Education and Research on Therapeutics |access-date=2010-07-04 |archive-url=https://web.archive.org/web/20101224200118/http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm |archive-date=2010-12-24 }}</ref> In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination.{{citation needed|date=February 2021}}

===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 blocker|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">{{Cite journal |last1=Mazzanti |first1=Andrea |last2=Maragna |first2=Riccardo |last3=Faragli |first3=Alessandro |last4=Monteforte |first4=Nicola |last5=Bloise |first5=Raffaella |last6=Memmi |first6=Mirella |last7=Novelli |first7=Valeria |last8=Baiardi |first8=Paola |last9=Bagnardi |first9=Vincenzo |last10=Etheridge |first10=Susan P. |last11=Napolitano |first11=Carlo |date=March 2016 |title=Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3 |journal=Journal of the American College of Cardiology |language=en |volume=67 |issue=9 |pages=1053–1058 |doi=10.1016/j.jacc.2015.12.033 |pmc=4773513 |pmid=26940925}}</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">{{cite journal |vauthors=Li G, Zhang L |date=November 2018 |title=The role of mexiletine in the management of long QT syndrome |journal=Journal of Electrocardiology |volume=51 |issue=6 |pages=1061–1065 |doi=10.1016/j.jelectrocard.2018.08.035 |pmid=30497731 |s2cid=54167081}}</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 [[Stellate ganglion|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">{{Cite journal |last1=Mazzanti |first1=Andrea |last2=Trancuccio |first2=Alessandro |last3=Kukavica |first3=Deni |last4=Pagan |first4=Eleonora |last5=Wang |first5=Meng |last6=Mohsin |first6=Muhammad |last7=Peterson |first7=Derick |last8=Bagnardi |first8=Vincenzo |last9=Zareba |first9=Wojciech |last10=Priori |first10=Silvia G |date=2022-04-05 |title=Independent validation and clinical implications of the risk prediction model for long QT syndrome (1-2-3-LQTS-Risk) |url=https://academic.oup.com/europace/article/24/4/614/6368300 |journal=EP Europace |language=en |volume=24 |issue=4 |pages=614–619 |doi=10.1093/europace/euab238 |pmid=34505884 |issn=1099-5129|url-access=subscription }}</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>{{cite journal | vauthors = Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, Keating MT, Mason JW | display-authors = 6 | title = Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium | journal = Circulation | volume = 94 | issue = 5 | pages = 1018–22 | date = September 1996 | pmid = 8790040 | doi = 10.1161/01.CIR.94.5.1018 | url = http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=8790040 | access-date = 2008-07-21 | archive-date = 2012-07-08 | archive-url = https://archive.today/20120708033139/http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=8790040 | url-access = subscription }}</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>{{Cite journal |last1=Zeppenfeld |first1=Katja |last2=Tfelt-Hansen |first2=Jacob |last3=de Riva |first3=Marta |last4=Winkel |first4=Bo Gregers |last5=Behr |first5=Elijah R. |last6=Blom |first6=Nico A. |last7=Charron |first7=Philippe |last8=Corrado |first8=Domenico |last9=Dagres |first9=Nikolaos |last10=de Chillou |first10=Christian |last11=Eckardt |first11=Lars |last12=Friede |first12=Tim |last13=Haugaa |first13=Kristina H. |last14=Hocini |first14=Mélèze |last15=Lambiase |first15=Pier D. |date=2022-10-21 |title=2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death |journal=European Heart Journal |volume=43 |issue=40 |pages=3997–4126 |doi=10.1093/eurheartj/ehac262 |issn=1522-9645 |pmid=36017572|hdl=1887/3567457 |hdl-access=free }}</ref> have endorsed the use of independently validated risk score calculator, called 1-2-3-LQTS-Risk Calculator,<ref>{{Cite journal |last1=Mazzanti |first1=Andrea |last2=Trancuccio |first2=Alessandro |last3=Kukavica |first3=Deni |last4=Pagan |first4=Eleonora |last5=Wang |first5=Meng |last6=Mohsin |first6=Muhammad |last7=Peterson |first7=Derick |last8=Bagnardi |first8=Vincenzo |last9=Zareba |first9=Wojciech |last10=Priori |first10=Silvia G. |date=2022-04-05 |title=Independent validation and clinical implications of the risk prediction model for long QT syndrome (1-2-3-LQTS-Risk) |journal=Europace |volume=24 |issue=4 |pages=614–619 |doi=10.1093/europace/euab238 |issn=1532-2092 |pmid=34505884}}</ref> which allows to calculate individual 5-year risk of life-threatening arrhythmic events.<ref>{{Cite web |title=1-2-3-LQTS-Risk |url=http://1-2-3-lqt.unipv.it/ |access-date=2024-01-17 |website=1-2-3-lqt.unipv.it}}</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">{{cite journal | vauthors = Giudicessi JR, Ackerman MJ | title = Genotype- and phenotype-guided management of congenital long QT syndrome | journal = Current Problems in Cardiology | volume = 38 | issue = 10 | pages = 417–55 | date = October 2013 | pmid = 24093767 | pmc = 3940076 | doi = 10.1016/j.cpcardiol.2013.08.001 }}</ref><ref>{{Cite web |url= https://ars.els-cdn.com/content/image/1-s2.0-S0146280613001217-gr6.jpg |title= Genotype risk relationship }}</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 [[Friedrich Ludwig Meissner|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'>{{cite journal | vauthors = Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M | title = Jervell and Lange-Nielsen syndrome: a Norwegian perspective | journal = American Journal of Medical Genetics | volume = 89 | issue = 3 | pages = 137–46 | date = September 1999 | pmid = 10704188 | doi = 10.1002/(SICI)1096-8628(19990924)89:3<137::AID-AJMG4>3.0.CO;2-C }}</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>{{cite journal | vauthors = Jervell A, Lange-Nielsen F | title = Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death | journal = American Heart Journal | volume = 54 | issue = 1 | pages = 59–68 | date = July 1957 | pmid = 13435203 | doi = 10.1016/0002-8703(57)90079-0 }}</ref> Italian pediatrician Cesarino Romano, in 1963,<ref>{{cite journal | vauthors = Romano C, Gemme G, Pongiglione R | title = [Arrythmias of the Pediatric Age. II. Syncopal Attacks Due to Paroxysmal Ventricular Fibrillation. Presentation of 1st Case in Italian Pediatric Literature] | language = it | journal = La Clinica Pediatrica | volume = 45 | pages = 656–83 | date = September 1963 | pmid = 14158288 }}</ref> and Irish pediatrician Owen Conor Ward, in 1964,<ref>{{cite journal | vauthors = Ward OC | title = A New Familial Cardiac Syndrome in Children | journal = Journal of the Irish Medical Association | volume = 54 | pages = 103–6 | date = April 1964 | pmid = 14136838 }}</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 [[Pedigree chart|pedigrees]] to be evaluated comprehensively.  This helped in detecting many of the genes involved.<ref>{{cite journal | vauthors = Moss AJ, Schwartz PJ | title = 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome | journal = Circulation | volume = 111 | issue = 9 | pages = 1199–201 | date = March 2005 | pmid = 15753228 | doi = 10.1161/01.CIR.0000157069.91834.DA | doi-access = free }}</ref> Transgenic animal models of the LQTS helped define the roles of various genes and hormones involved,<ref>{{Cite journal|last1=Brunner|first1=Michael|last2=Peng|first2=Xuwen|last3=Liu|first3=Gong Xin|last4=Ren|first4=Xiao-Qin|last5=Ziv|first5=Ohad|last6=Choi|first6=Bum-Rak|last7=Mathur|first7=Rajesh|last8=Hajjiri|first8=Mohammed|last9=Odening|first9=Katja E.|last10=Steinberg|first10=Eric|last11=Folco|first11=Eduardo J.|date=June 2008|title=Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome|journal=The Journal of Clinical Investigation|volume=118|issue=6|pages=2246–2259|doi=10.1172/JCI33578|issn=0021-9738|pmc=2373420|pmid=18464931}}</ref><ref>{{cite journal |last1=Hornyik |first1=Tibor |last2=Rieder |first2=Marina |last3=Castiglione |first3=Alessandro |last4=Major |first4=Peter |last5=Baczko |first5=Istvan |last6=Brunner |first6=Michael |last7=Koren |first7=Gideon |last8=Odening |first8=Katja E. |title=Transgenic rabbit models for cardiac disease research |journal=British Journal of Pharmacology |date=10 May 2021 |volume=179 |issue=5 |pages=938–957 |doi=10.1111/bph.15484|pmid=33822374 |s2cid=233036129 |url=http://publicatio.bibl.u-szeged.hu/22548/1/HornyikBritJPharmacol2021.pdf }}</ref> and recently experimental [[Pharmacological therapy|pharmacological therapies]] to normalize the abnormal repolarization in animals were published.<ref>{{cite journal |last1=Bentzen |first1=Bo Hjorth |last2=Bahrke |first2=Sophia |last3=Wu |first3=Kezhong |last4=Larsen |first4=Anders Peter |last5=Odening |first5=Katja E |last6=Franke |first6=Gerlind |last7=van´s Gravesande |first7=Karin Storm |last8=Biermann |first8=Jürgen |last9=Peng |first9=Xuwen |last10=Koren |first10=Gideon |last11=Zehender |first11=Manfred |last12=Bode |first12=Christoph |last13=Grunnet |first13=Morten |last14=Brunner |first14=Michael |title=Pharmacological Activation of Kv11.1 in Transgenic Long QT-1 Rabbits |journal=Journal of Cardiovascular Pharmacology |date=February 2011 |volume=57 |issue=2 |pages=223–230 |doi=10.1097/FJC.0b013e318203a44d|pmid=21135701 |s2cid=3282707 }}</ref><ref>{{cite journal |last1=Castiglione |first1=Alessandro |last2=Hornyik |first2=Tibor |last3=Wülfers |first3=Eike M |last4=Giammarino |first4=Lucilla |last5=Edler |first5=Iask |last6=Jowais |first6=Jessica J |last7=Rieder |first7=Marina |last8=Perez-Feliz |first8=Stefanie |last9=Koren |first9=Gideon |last10=Bősze |first10=Zsuzsanna |last11=Varró |first11=András |last12=Zehender |first12=Manfred |last13=Brunner |first13=Michael |last14=Bode |first14=Christoph |last15=Liin |first15=Sara I |last16=Larsson |first16=Hans Peter |last17=Baczkó |first17=István |last18=Odening |first18=Katja E |title=Docosahexaenoic acid normalizes QT interval in long QT type 2 transgenic rabbit models in a genotype-specific fashion |journal=EP Europace |date=3 October 2021 |volume=24 |issue=3 |pages=511–522 |doi=10.1093/europace/euab228|pmid=34601592 |pmc=9125797 }}</ref>

== References ==
=== Citations ===
{{Reflist}}

=== General and cited references ===
* {{cite book |last1 = Goldman |first1 = Lee | name-list-style = vanc |title = Goldman's Cecil Medicine |publisher  = Elsevier Saunders |location = Philadelphia |isbn = 978-1-4377-2788-3 |year = 2011 |pages = 1196 |edition = 24th }}

{{Medical resources
| DiseasesDB      = 11104
| ICD10           = {{ICD10|I|45|8|i|30}}
| ICD9            = {{ICD9|426.82}}
| ICDO            =
| OMIM            =
| MedlinePlus     =
| eMedicineSubj   = med
| eMedicineTopic  = 1983
| MeshID          = D008133
| SNOMED CT       = 9651007
}}
{{Circulatory system pathology}}
{{Channelopathy}}
{{Inherited disorders of trafficking}}
{{Cytoskeletal defects}}

[[Category:Cardiac arrhythmia]]
[[Category:Cardiogenetic disorders]]
[[Category:Channelopathies]]
[[Category:Cytoskeletal defects]]
[[Category:Single-nucleotide polymorphism associated disease]]
[[Category:Syndromes affecting the heart]]
[[Category:Wikipedia medicine articles ready to translate]]