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{{DevelopmentPhase}}
<i>Auteur: Louise R.A. Olde Nordkamp</i>


The '''Long QT Syndrome (LQTS)''' refers to a condition in which there is an abnormally long QT interval on the ECG. This was first recognized by Dr. Jervell and Dr. Lange-Nielsen in 1957. They described 4 children with a long QT interval which was accompanied by hearing deficits, sudden cardiac death and an autosomal recessive inheritance. <cite>Lang1957</cite>
<i>Supervisor: Arthur A.M. Wilde</i>


The LQTS may be divided into two distinct forms: congenital LQTS and acquired LQTS. These forms may however overlap when QT prolongation due to medication occurs in a patient with congenital LQTS.  
The '''Long QT Syndrome (LQTS)''' refers to a condition in which there is an abnormally long QT interval on the ECG. This was first recognized by Dr. Jervell
 
and Dr. Lange-Nielsen in 1957. They described 4 children with a long QT interval which was accompanied by hearing deficits, sudden cardiac death and an
 
autosomal recessive inheritance.
 
[[Image:De-Formule QTc.png|right|thumb|Formula for heart rate corrected QT interval (Bazett’s formula)]]
The LQTS may be divided into two distinct forms: congenital LQTS and acquired LQTS. These forms may however overlap when QT prolongation due to medication  
 
occurs in a patient with congenital LQTS.  


==Diagnosis==
==Diagnosis==
===General===
===General===
[[Image:De-Formule QTc.png|right|thumb|Formula for heart rate corrected QT interval (Bazett’s formula)]]
*The diagnosis is by measurement of the heart rate corrected QT interval on the ECG, which can be calculated with the [[QTc calculator]].  
*The diagnosis is by measurement of the heart rate corrected QT interval on the ECG, which can be calculated with the [[QTc calculator]].  
*Sometimes the QT interval can be difficult to assess. Read the [[guidelines for measurement of difficult QT interval]].  
*Sometimes the QT interval can be difficult to assess. Read the [[guidelines for measurement of difficult QT interval]].  
*A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk of torsade de pointes and sudden death. <cite>priori</cite>
*A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk of torsade de pointes and sudden death.<cite>priori</cite>
*In patients suspected of LQTS (e.g. family members of known LQTS patients) a QTc > 430ms makes it likely that a LQTS gene defect is present.<cite>Hofman</cite>
*In patients suspected of LQTS (e.g. family members of known genotyped LQTS patients) a QTc > 430ms makes it likely that a LQTS gene defect is present.
*Because the QTc can change with age, it is best to take the ECG with the longest QTc interval for risk stratification. <cite>Goldenberg</cite>
*Because the QTc can change with age, it is best to take the ECG with the longest QTc interval (without additional QT-prologing factors) for risk  
 
stratification.


===Physical examination===
===Physical examination===
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
[[Image:Torsade_de_Pointes.png|right|thumb]]
|-
Patients can present with symptoms of arrhythmias:
!Patients can present with symptoms of arrhythmias:
|-
|
*Fast or slow heart beat
*Fast or slow heart beat
*Skipping beats
*Weakness, lightheadedness, dizziness, syncope
*Weakness, lightheadedness, dizziness, syncope
*Chest pain
*Chest pain
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*Paleness
*Paleness
*Sweating
*Sweating
|}
 
==Acquired LQTS==
==Acquired LQTS==
Acquired LQTS is most often caused by drugs that prolong the QT interval; combined with risk factors the risk of [[Torsade de Pointes]] is likely to increase.


Acquired LQTS is most often caused by drugs that prolong the QT interval; combined with risk factors the risk of [[Torsade de Pointes]] is likely to
increase.
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
|-
|-
!
!
===Notorious QT prolonging drugs:<cite>Roden</cite>===
===Notorious QT prolonging drugs:===
|-
|-
|
|
#Amiodarone
#Amiodarone
#Azithromycin
#Chloroquine
#Chloroquine
#Chlorpromazine
#Chlorpromazine
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#Halofantrine
#Halofantrine
#Haloperidol
#Haloperidol
#Procainamide
#Quinidine
#Quinidine
#Sotalol
#Sotalol
Line 72: Line 79:


|}
|}


==Congenital LQTS==
==Congenital LQTS==
The prevalence of congenital LQTS is about 1:3000-5000. More than 10 different types of congenital LQTS have been described. However, only LQTS 1-3 are relatively common. <cite>ACC2006</cite>


The three most common forms of LQTS can be recognized by the characteristic clinical features and ECG abnormalities.
The prevalence of congenital LQTS is about 1:2000-2500. More than 10 different types of congenital LQTS have been described. However, only LQTS 1-3 are
 
relatively common.
 
The three most common forms of LQTS can be recognized by the characteristic clinical features and ECG abnormalities  


{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
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|'''B-blokker efficacy'''
|'''B-blokker efficacy'''
| ++++
| ++++
| +
| +++
| ±
| ++
|-
|-
|'''ECG'''
|'''ECG'''
|''Early onset''  
|''Early onset'' broad based T wave
broad based T wave
|Small late T wave
|Small late T wave
|''Late onset''  
|''Late onset'' T wave with normal configuration
T wave with normal configuration
|-
|-
|'''Arrhythmogenic triggers'''
|'''Arrhythmogenic triggers'''
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|Adrenergic triggers, especially nightly noise
|Adrenergic triggers, especially nightly noise
|Rest
|Rest
|-
|'''Number of mutation carriers with events at age <15'''
|40%
|20%
|10%
|-
|-
|'''Number of mutation carriers with events at age <40'''
|'''Number of mutation carriers with events at age <40'''
|25%
|60%
|50%
|60%
|50%
|50%
|-
|-
|'''SCD incidence'''
|'''Sudden cardiac death incidence Eponyme'''
|0,30% / year
|0,30% / year
|0,60% / year
|0,60% / year
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|-
|-
|'''Eponyme'''
|'''Eponyme'''
|If condition is homozygous:  
|If condition is homozygous: Jervell and Lange-Nielsen syndrome 1
Jervell and Lange-Nielsen syndrome 1
|If condition is homozygous:
Jervell and Lange-Nielsen syndrome 2
|
|
|}
|}


Before the genes involved were known, some syndromes associated with a prolonged QT interval on the ECG had been described earlier:
Before the genes involved were known, some syndromes associated with a prolonged QT interval on the ECG had been described earlier:
*Anton Jervell and Fred Lange-Nielsen from Oslo described in 1957 an congenital syndrome that was associated with QT interval prolongation, deafness and


*Anton Jervell and Fred Lange-Nielsen <cite>Lang1957</cite> from Oslo described in 1957 an autosomaal recessive syndrome that was associated with QT interval prolongation, deafness and sudden death: the now called Jervell-Lange-Nielsen syndrome.
sudden death: the now called Jervell-Lange-Nielsen syndrome.
*Romano-Ward syndrome is a long QT syndrome with normal auditory function and autosomal dominant inheritance.<cite>Alders</cite>  
*Andersen-Tawil syndrome was described in 1994 by Tawil et al. and was associated with potassium-sensitive periodic paralysis, ventricular ectopy and  


*Romano-Ward syndrome is a long QT syndrome with normal auditory function and autosomal dominant inheritance.  
dysmorphic features (short stature, low-set ears, hypoplastic mandible, clinodactyly and scoliosis). It later appeared to be associated with a mutation in


*Andersen-Tawil syndrome was described in 1994 by Tawil et al. and was associated with potassium-sensitive periodic paralysis, ventricular ectopy and dysmorphic features (short stature, low-set ears, hypoplastic mandible, clinodactyly and scoliosis). It later appeared to be associated with a mutation in the KCNJ2 gene (LQTS type 7).
the KCNJ2 gene (LQTS type 7).
*Timothy syndrome is a LQTS syndrome (with frequently alternating T-waves) with webbing of fingers and toes, congenital heart disease, immune deficiency,


*Timothy syndrome is a LQTS syndrome (with frequently alternating T-waves) with webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycaemia, cognitive abnormalities and autism. It appeared to be caused by mutations in the CACNA1C gene (LQTS type 8).
intermittent hypoglycaemia, cognitive abnormalities and autism. It appeared to be caused by a single mutation in the CACNA1C gene (LQTS type 8).
 
===Clinical diagnosis===
Diagnosis of LQTS is established by prolongation of the QTc interval in the absence of specific conditions known to lengthen it (for example QT-prolonging drugs) and/or molecular genetic testing of genes associated with LQTS.  


{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width=""600px"
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width=""600px"
|-
!colspan="4"|Diagnostic criteria by Schwartz et al.
|-
|-
|'''Findings'''
|'''Findings'''
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460-479
460-479


450-459
450-459 (in males)


>480 during  
>480 during  
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|}
|}


[[Image:LQTS_triggers.svg|thumb|400px|Various triggers for cardiac events have been identified among the different genotypes.]]
==Clinical diagnosis==
 
Diagnosis of LQTS is established by prolongation of the QTc interval in the absence of specific conditions known to lengthen it (for example QT-prolonging
 
drugs) and/or molecular genetic testing of genes associated with LQTS.
 
The prolonged QT interval can cause torsades de pointes, which is usually self-terminating, thus potentially causing a cardiac syncopal event. In LQTS type
 
1, cardiac symptoms are often precipitated by exercise; especially swimming is notorious for life-threatening cardiac events. In LQTS type 2, arrhythmogenic
 
triggers are adrenergic; especially nightly noise (such as the morning alarm clock or nightly thunderlightening) is known to cause life-threatening cardiac


The prolonged QT interval can cause torsade de pointes, which is usually self-terminating, thus causing a cardiac syncopal event. The mean age of onset of symptoms (syncope or sudden death) is 12 years and earlier onset is usually associated with more severe form of the disease. In LQTS type 1, cardiac symptoms are often precipitated by exercise; especially swimming is notorious for life-threatening cardiac events. In LQTS type 2, arrhythmogenic triggers are adrenergic; especially nightly noise (such as the morning alarm clock or nightly thunderlightening) is known to cause life-threatening cardiac events. On the other hand, in LQTS type 3, QT prolongation and possibly subsequent torsade de pointes is precipitated by bradycardia.
events. On the other hand, in LQTS type 3, QT prolongation and possibly subsequent torsade de pointes is precipitated by bradycardia.  


===ECG tests===
[[Image:LQTS_triggers.svg|thumb|right|400px|Various triggers for cardiac events have been identified among the different genotypes.]]
[[Image:Lqts1-3.png|right|thumb|400px|Various ECG patterns can be recognized among the different genotypes. '''LQT1''' is characterised by prolonged QT intervals associated with a broad-based T wave. '''LQT2'''  is characterised by low-amplitude and notched T waves. '''LQT3'''  is characterised by long ST segments with a late-appearing T wave resulting in a long QT interval.]]


==ECG tests==
ECGs can be difficult because there is a considerable overlap between the QT interval of affected and unaffected individuals.
ECGs can be difficult because there is a considerable overlap between the QT interval of affected and unaffected individuals.


*The resting ECG is neither completely sensitive nor specific for the diagnosis of LQTS. The diagnostic criteria for the resting ECG are shown in the list of diagnostic criteria by Schwartz. Besides a prolonged QTc, the T-wave can have different patterns among the different genotypes.
*The resting ECG is neither completely sensitive nor specific for the diagnosis of LQTS. The diagnostic criteria for the resting ECG are shown above in the  


list of diagnostic criteria by Schwartz et al. Besides a prolonged QTc, the T-wave can have different patterns among the different genotypes.
*Holter recordings appear to be of minimal clinical utility from a diagnostic and prognostic prospective in evaluating LQTS
*Holter recordings appear to be of minimal clinical utility from a diagnostic and prognostic prospective in evaluating LQTS
*The exercise ECG (X-ECG) commonly shows failure of the QT to shorten normally, thereby prolonging the corrected QT interval, and many individuals develop


*The exercise ECG (X-ECG) commonly shows failure of the QT to shorten normally, thereby prolonging the corrected QT interval, and many individuals develop characteristic T-wave abnormalities.  
characteristic T-wave abnormalities.
*A brisk-standing test ECG, where the QT-interval is measured after abrupt standing with subsequent heart rate acceleration. There appears to be a form of


*A brisk-standing test ECG, where the QT-interval is measured after abrupt standing with subsequent heart rate acceleration. There appears to be a form of QT-stretching and QT-stunning. <cite>Viskin</cite><cite>Adler</cite>
QT-stretching and QT-stunning <cite>Adler</cite> as demonstrated by Viskin et al. and Adler et al.
*Epinephrine infusion is a provocative test that might increase the sensitivity of the ECG findings. However, especially the negative predictive value is


*Epinephrine infusion is a provocative test that increases the sensitivity of the ECG findings
high.
*Adenosine infusion is a test provoking transient bradycardia followed by sinus tachycardia and therefore triggers QT changes that can distinguish patients
 
with LQTS from healthy controls<cite>adenosine</cite>
[[Image:Lqts1-3.png|thumb|right|400px|Various triggers for cardiac events have been identified among the different genotypes.]]


*Adenosine infusion is a test provoking transient bradycardia followed by sinus tachycardia and therefore triggers QT changes that can distinguish patients with LQTS from healthy controls
<gallery>
File:Lqts1.png|A 12 lead ECG of a patient with genetically proven LQTS1
File:Lqts2.png|A 12 lead ECG of a patient with genetically proven LQTS2
File:Lqts3.png|A 12 lead ECG of a patient with genetically proven LQTS3
</gallery>


==Genetic diagnosis==
==Genetic diagnosis==
Today, 13 LQTS genes associated with LQTS have been identified. Most commonly, KCNQ1, KCNH2 and SCN5A, which are associated with LQTS type 1, type 2 and type 3 respectively, are found. Other, less frequently involved genes are displayed the table below.  
 
Today, 14 LQTS genes associated with LQTS have been identified. Most commonly, KCNQ1, KCNH2 and SCN5A, which are associated with LQTS type 1, type 2 and type  
 
3 respectively, are found. Other, less frequently involved genes are displayed the table below.
 
There is an important genotype-phenotype relationship on severity of the disease.<cite>Schwartz2001</cite> In genotype–phenotype studies in the Rochester
 
LQTS registry it was shown that in both LQTS type 1 and type 2, mutation locations and the degree of ion channel dysfunction caused by the mutations are
 
important independent risk factors influencing the clinical course of this disorder.


{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
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|Kir3.4 (I<sub>K</sub>)
|Kir3.4 (I<sub>K</sub>)
|600734
|600734
|-
|Type 14
|CALM1
|Calmodulin 1
|114180
|}
|}


There is an important genotype-phenotype relationship on severity of the disease. In genotype–phenotype studies in the Rochester LQTS registry it was shown that in both LQTS type 1 and type 2, mutation locations and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.


==Risk Stratification==
==Risk Stratification==
Gene-specific differences of the natural history of LQTS have also been demonstrated and allow genotype-based risk stratification. Indeed, QT interval duration, gender and genotype (including mutation location and degree of ion channel dysfunction) are significantly associated with the outcome, with a QTc interval >500ms, and a LQT2 or LQT3 genotype determining the worst prognosis. Gender differently modulates the outcome according to the underlying genetic defect: the LQT3 males and LQT2 females are the highest risk subgroups. Risk stratification is best done by an expert cardio-genetics cardiologist.


==Treatment <cite>ACC2006</cite>==
Gene-specific differences of the natural history of LQTS have also been demonstrated and allow genotype-based risk stratification. Indeed, QT interval
===Lifestyle modification===  
 
*No competitive sports in all LQTS patients  
duration, gender and genotype (including mutation location and degree of ion channel dysfunction) are significantly associated with the outcome, with a QTc
 
interval >500ms, and a LQT2 or LQT3 genotype determining the worst prognosis. Gender differently modulates the outcome according to the underlying genetic
 
defect: the LQT3 males and LQT2 females are the highest risk subgroups. Risk stratification is best done by an expert cardio-genetics cardiologist.
 
==Treatment==
 
==="Lifestyle modification":===  
*Probably no competitive sports in all LQTS patients  
*Avoid QT-prolonging drugs in all LQTS patients
*Avoid QT-prolonging drugs in all LQTS patients
*No swimming in LQT1 patients  
*No swimming or diving  in LQT1 patients  
*Avoid nightly noise in LQT2 patients (e.g. no alarm clock)  
*Avoid nightly or sudden noise in LQT2 patients (e.g. no alarm clock)  


===Medication/Other therapies===  
===Medication/Other therapies:===  
*Beta-blockers are the cornerstone of therapy in LQTS. Beta-blockers even reduce the risk of sudden death in patients in whom a genetic defect has been found, but no QT prolongation is visible on the ECG and probably even in LQTS3 patients with bradycardia-associated cardiac events. In symptomatic patients propranolol and nadolol are equally effective, but a recent retrospective study showed that metoprolol should not be used for symptomatic LQT1 and LQT2 patients.<cite>Wilde</cite>
*Beta-blockers are the cornerstone of therapy in LQTS. Beta-blockers even reduce the risk of sudden death in patients in whom a genetic defect has been  


*[[ICD]] implantation in combination with beta-blockers in LQTS patients with previous cardiac arrest, cardiac [[syncope]] or [[tachycardia|ventricular tachycardia]] while on beta-blockers. Symptomatic patients with LQTS type 3 can only be treated with an ICD with pacing possibilities, since their arrhythmic episodes are bradycardia-associated.  
found, but no QT prolongation is visible on the ECG and also in LQTS3 patients with bradycardia-associated cardiac events <cite>congenital</cite>
*[[ICD]] implantation in combination with beta-blockers in LQTS patients with previous cardiac arrest, cardiac [[syncope]] or [[ventricular tachycardia]]  
 
while on beta-blockers. ICDs should have pacing possibilities, because arrhythmic episodes are bradycardia-associated in LQTS type 3 and since post-shock
 
pacing is relevant in all other LQTS types.
*Cardiac sympathetic denervation (LCSD) should be considered in the setting of beta-blocker breakthroughs, intolerance to pharmacotherapy and history of
 
appropriate ICD therapies. Surgically, LCSD involves the resection of the lower two-third of the left stellate ganglion and the left-sided sympathetic chain
 
at the level of T2, T3 and T4.  


*Cardiac sympathetic denervation (LCSD) should be considered in the setting of beta-blocker breakthroughs, intolerance to pharmacotherapy and history of appropriate ICD therapies. Surgically, LCSD involves the resection of the lower half of the left stellate ganglion and the left-sided sympathetic chain at the level of T2, T3 and T4.


==References==
==References==
<biblio>
<biblio>
#Schwartz2001 pmid=11136691
#Schwartz2001 pmid=11136691
#Shah2005 pmid=16230503
#priori pmid=12736279
#Lang1957 pmid=13435203
#genotype pmid=19926013
#ACC2006 pmid=16935995
#Goldenberg pmid=16949500
#Roden pmid=14999113
#moss pmid=17470695
#moss pmid=17470695
#priori pmid=12736279
#Hofman pmid=17090615
#Roden1 pmid=18184962
#Alders pmid=20301308
#Alders pmid=20301308
#Shimizu Shimizu W, Moss AJ, Wilde AA, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009; 54:2052-62.
#probands pmid=22042885
#Sy Sy RW, van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 2011; 124:2187-94.
#QTc pmid=22083145
#Schwartz Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124:2181-4.
#LongQT pmid=20116193
#Viskin Viskin S, Postema PG, Bhuiyan ZA, et al. The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010; 55:1955-61.
#Adler pmid=22300664
#Adler Adler A, van der Werf C, Postema PG, et al. The phenomenon of "QT stunning": The abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome. Heart Rhythm 2012; 9:901-8.
#congenital pmid=15851169
#Shimizu1 Shimizu W, Noda T, Takaki H, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm 2004; 1:276-83.
#adenosine pmid=16105845
#Viskin1 Viskin S, Rosso R, Rogowski O, et al. Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome. Eur Heart J 2006; 27:469-75.
#Wilde pmid=23083782
</biblio>
</biblio>
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