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[[Image:acquired_longQT.jpg|thumb|A 12-lead ECG of a patient with acquired long QT syndrome. Notice the QT prolongation. The QTc is about 640ms.]]
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>
The '''Long QT Syndrome (LQTS)''' is characterized on the ECG by prolongation of the [[Conduction#The_QT_interval|heart rate corrected QT interval]]. 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>


The Long QT syndrome may be divided into two distinct forms: congenital Long QT syndrome and acquired Long QT syndrome. These forms may however overlap when QT prolongation due to medication occurs in a patient with congenital Long QT syndrome.
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==
*The diagnosis is by measurement of the [[Conduction#The_QT_interval|heart rate-corrected QT interval]] on the ECG, which can be calculated with the [[QTc calculator]].
===General===
*Sometimes the QT interval can be difficult to assess. Read the [[Difficult_QT|guidelines for measurement of difficult QT interval]].
[[Image: |right|200px|Formula for heart rate corrected QT interval (Bazett’s formula):]]
*A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk for sudden death.<cite>Priori</cite>  
 
*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]].  
*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 LQTS patients) a QTc > 430ms makes it likely that a LQTS gene defect is present.<cite>Hofman</cite>
*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 for risk stratification. <cite>Goldenberg</cite>
 
===Physical examination===
Patients can present with symptoms of arrhythmias:
*Fast or slow heart beat
*Skipping beats
*Weakness, lightheadedness, dizziness, syncope
*Chest pain
*Shortness of breath
*Paleness
*Sweating
 
==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.
 
===Notorious QT prolonging drugs: <cite>Roden</cite>===
#Amiodarone
#Azithromycin
#Chloroquine
#Chlorpromazine
#Citalopram
#Claritromycin
#Disopyramide
#Dofetilide
#Erythromycin
#Flecainide
#Halofantrine
#Haloperidol
#Procainamide
#Quinidine
#Sotalol
 
===Concomittant risk factors for medication induced torsade de pointes:===
#Female sex
#Hypokalemia
#Bradycardia
#Recent conversion of atrial fibrillation, especially if QT prolonging drugs were used (sotalol, amiodarone)
#Cardiac decompensation
#Digoxin treatment
#High or overdosing or rapid infusion of a QT prolonging drug
#Pre-existing QT prolongation
#Congenital QT syndrome


===Treatment<cite>ACC2006</cite>===
==Congenital LQTS==
*"Lifestyle modification":
** No competitive sports in all LQTS patients
** No swimming in LQT1 patients
** Avoid nightly noise in LQT2 patients (e.g. no alarm clock)
*Medication: beta-blockers. 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.
*[[:w:nl:Internal_Cardiac_Defibrillator|ICD]] implantation in combination with beta-blockers in LQTS patients with previous cardiac arrest or [[syncope]] or [[Ventricular Tachycardia|ventricular tachycardia]] while on beta-blockers.


===Acquired 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>
Acquired LQTS is most often caused by drugs that prolong the QT interval. Combined with risk factors (see table) the risk of [[Torsade_de_Pointes|Torsade de Pointes]] increases.


{|  
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="100%"
|-
!LQTS type
!LQTS 1
!LQTS 2
!LQTS 3
|-
|'''Gene/current'''
|KCNQ1/IK<sub>s</sub>
|KCNH2/IK<sub>r</sub>
|SCN5A/INa
|-
|'''B-blokker efficacy'''
| ++++
| +
| ±
|-
|'''ECG'''
|“Early onset” broad based T wave
|Small late T wave
|“Late onset”
T wave with normal configuration
|-
|-
|valign="top"|
|'''Arrhythmogenic triggers'''
{| class="wikitable" width="400px"
|Exercise, especially swimming
!Common drugs that can cause [[Torsade_de_Pointes|Torsade de Pointes]] include:<cite>Roden</cite>
|Adrenergic triggers, especially nightly noise
|Rest
|-
|-
|'''Number of mutation carriers with events at age <40'''
|25%
|50%
|50%
|-
|'''SCD incidence'''
|0,30% / year
|0,60% / year
|0,56% / year
|-
|'''Eponyme'''
|If condition is homozygous: Jervell and Lange-Nielsen syndrome 1
|If condition is homozygous: Jervell and Lange-Nielsen syndrome 2
|
|
<ul>
|}
<li>Sotalol</li>
 
<li>Amiodarone</li>
Before the genes involved were known, some syndromes associated with a prolonged QT interval on the ECG had been described earlier:
<li>Erythromycin</li>
 
<li>Clarithromycin</li>
*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.
</ul>
 
*Romano-Ward syndrome is a long QT syndrome with normal auditory function and autosomal dominant inheritance.
 
*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).
 
*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).
 
===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="100%"
|-
|-
!Less often used drugs include:
!colspan="4"|Diagnostic criteria by Schwartz et al.
|-
|-
|'''Findings'''
|
|
<ul>
|
<li>Cisapride</li>
|'''Points'''
<li>antibiotics: halofantrine, pentamidine, sparfloxacin</li>
|-
<li>Anti-emetics: domperidon, droperidol</li>
|'''ECG'''
<li>Anti-psychotics: chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide</li>
|QTc:
<li>Methadon</li>
|>480 ms
<li>Disopyramide</li>
 
<li>Dofetilide</li>
460-479
<li>Ibutilide</li>
 
<li>Procainamide</li>
450-459
<li>Quinidine</li>
 
<li>Bepridil</li>
>480 during
</ul>
 
X-ECG
|valign="top"|3
 
2
 
1
 
1
|-
|-
|[http://www.torsades.org Torsades.org] has an extensive list of drugs that can TdP
|
|}
|colspan="2"|Torsade de pointes
|valign="top"|
 
{| class="wikitable" align="right" width="400px"
T-wave alternans
!Concomittant risk factors for medication induced [[Torsade_de_Pointes|Torsade de Pointes]]:
 
Notched T-wave in 3 leads
 
Low heart rate for age (<2<sup>nd</sup> percentile for age)
|2
 
1
 
1
 
0.5
|-
|-
|
|
<ul>
|Syncope:
<li>Female sex</li>
|With stress
<li>Hypokalemia</li>
Without stress
<li>Bradycardia</li>
|2
<li>Recent conversion of [[Atrial Fibrillation|atrial fibrillation]], especially if QT prolonging drugs were used (sotalol, amiodarone)</li>
1
<li>Cardiac decompensation</li>
|-
<li>Digoxin treatment</li>
|'''Clinical history'''
<li>High or overdosing or rapid infusion of a QT prolonging drug</li>
|colspan="2"|Congenital deafness
<li>Pre-existing QT prolongation</li>
Family members with definite LQTS
<li>Congenital long QT syndrome</li>
|0.5
</ul>
1
|}
|-
|'''Family history'''
|colspan="2"|Unexplained sudden cardiac death before age 30
|0.5
|-
|-
|colspan="4"|''Total score =1 Low probability; 1.5-3 Intermediate probability; =3.5 High probability''
|}
|}


===Congenital LQTS===
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.
[[Image:lqts1-3.png|thumb|The three most common forms of LQTS can be recognized by the '''characteristic ECG abnormalities''']]:
 
*LQT1 'early onset' broad based T wave
===ECG tests===
*LQT2 small late T wave
[[Image: |right|thumb|Various ECG patterns can be recognized among the different genotypes]]
*LQT3 prolonged QT interval with 'late onset' T wave with a normal configuration
ECGs can be difficult because there is a considerable overlap between the QT interval of affected and unaffected individuals.
In congenital LQTS the ventricular repolarisation is prolonged. '''The prevalence is about 1:3000-5000'''.  
 
*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.
 
*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 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 QT-stretching and QT-stunning as demonstrated by Viskin et al. and Adler et al.


More than 10 different types of congenital LQTS have been described. However, only LQTS 1-3 are relatively common.<cite>ACC2006</cite>
*Epinephrine infusion is a provocative test that increases the sensitivity of the ECG findings


{| border="1" cellpadding="2" cellspacing="0" bordercolor="#6EB4EB" style="font-size:100%;" class="plainlinks" class="wikitable"
*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
|- style="text-align:center;background-color:#6EB4EB;"
 
| '''Type'''
==Genetic diagnosis==
| '''Chromosome'''
 
| '''Gene'''
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.
| '''Protein'''
 
| '''Ionchannel'''
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="100%"
| '''Frequency<cite>priori</cite>'''
|-
| '''SCD incidence<cite>Shah2005</cite>'''
!LQTS type
| '''Inheritance'''
!Gene
| '''ECG characteristics'''
!Protein (Ionchannel)
| '''Trigger'''
!OMIM-link
| '''Eponyme'''
|-
| '''[[w:OMIM|OMIM&trade;]] link'''
|Type 1
|KCNQ1
|KVLQT1 (I<sub>Ks<sub>)
|607542
|-
|-
! LQTS1
|Type 2
| 11p15
|KCNH2
| KCNQ1
|HERG (I<sub>Kr</sub>)
| KvLQT1
|613688
| I''ks''
| ~50%
| 0.30%/year
| AD, AR
| broad base 'early onset' T wave
| exercise, especially swimming
| JLN1 if homozygous, LQTS1 if heterozygous
| {{OMIM2|607542}}
|-
|-
! LQTS2
|Type 3
| 7q35
|SCN5A
| KCNH2
|Sodium channel (I<sub>Na</sub>)
| hERG
|603830
| I''kr''
| 30-40%
| 0.60%/year
| AD
| small late T wave
| adrenergic triggers, especially nightly noise
| JLN2 if homozygous, LQTS2 if heterozygous
| {{OMIM2|152427}}
|-
|-
! LQTS3
|Type 4
| 3p21
|ANK2
| SCN5A
|Ankyrin B (I<sub>Na, K</sub>)
| NA channel
|600919
|
|-
| 5-10%
|Type 5
| 0.56%/year
|KCNE1
| AD
|minK (I<sub>Ks</sub>)
| 'Late onset' T wave with normal configuration
|176261
|
|
| {{OMIM2|600163}}
|-
|-
! LQTS4
|Type 6
| 4q25-q27
|KCNE2
| ANK2
|MiRP1 (I<sub>Kr</sub>)
| Ankyrin B
|613693
| I''Na,K''
| <1%
|
| AD
|
|
|
| {{OMIM2|106410}}
|-
|-
! LQTS5
|Type 7
| 21q22.1
|KCNJ2
| KCNE1
|Kir 2.1 (I<sub>K1</sub>)
| minK
|170390
| I''ks''
| <1%
| unknown
| AD/AR
|
|
|
| {{OMIM2|176261}}
|-
|-
! LQTS6
|Type 8
| 21q22.1
|CACNA1C
| KCNE2
|Ca<sub>v</sub>1.2 (I<sub>Ca-L</sub>)
| MiRP1
|601005
| I''kr''
| <1%
| unknown
| AD
|
|
|
| {{OMIM2|603796}}
|-
|-
! LQTS7 = ATS1
|Type 9
| 17q23
|CAV3
| KCNJ2
|Caveolin-3
| Kir 2.1
|601253
| I''K1''
| <1%
| unknown
| AD
|
|
| Anderson-Tawil syndrome
| {{OMIM2|600681}}
|-
|-
! LQTS8 = TS1
|Type 10
| 12p13.3
|SCN4B
| CACNA1C
|Sodium channel (I<sub>Na</sub>)
| Ca<sub>v</sub>1.2
|608256
| I''Ca-L''
| <1%
| unknown
|
| alternating T waves
|
| Timothy syndrome
| {{OMIM2|601005}}
|-
|-
! LQTS9
|Type 11
| 3p25.3
|AKAP9
| CAV3
|A-Kinase anchor 9 (I<sub>Ks</sub>)
| Caveolin 3
|604001
| I''Na''
|
| unknown
|
|
|
|
| {{OMIM2|601253}}
|-
|-
! LQTS10
|Type 12
| 11q23.3
|SNTA1
| SCN4B
|Syntrophin (I<sub>Na</sub>)
| Na<sub>v</sub>1.5 b4
|601017
|
| 1 family
| unknown
|
|  
|
|
| {{OMIM2|608256}}
|-
|-
! LQTS11
|Type 13
| 7q21-q22
|KCNJ5
| Akap9
|Kir3.4 (I<sub>K</sub>)
| AKAP
|600734
| I''ks''
| 1 family
| unknown
|
|
|
|
| {{OMIM2|611820}}
|}
|}
;LQTS: Long QT syndrome
 
;JLN: Jervell and Lange-Nielsen syndrome
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.
;SCD: Sudden Cardiac Death
 
==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>==
 
===Lifestyle modification===
*No competitive sports in all LQTS patients
*Avoid QT-prolonging drugs in all LQTS patients
*No swimming in LQT1 patients
*Avoid nightly noise in LQT2 patients (e.g. no alarm clock)
 
===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
 
*[[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.
 
*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.
   
   
Long before the genes involved were known, two syndromes  associated with a prolonged QT interval on the ECG had been described.
==References==
* Anton Jervell and Fred Lange-Nielsen 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'''. <cite>Lang1957</cite>
* '''Romano-Ward syndrome''' is a long QT syndrome with normal auditory function and autosomal dominant inheritance.
* In a genotype–phenotype study by Moss et al. that studied type-1 LQTS, it was found that mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.<cite>moss</cite>


==External links==
#[http://www.torsades.org Torsades.org has a list of QT prolonging drugs]
#[http://qtdrugs.org QTdrugs.org, another list of QT prolonging drugs]
#[http://www.sads.org Sudden Arrhythmia Death Syndrome Foundation]. LQTS patient group.
#[http://www.fsm.it/cardmoc/ Inherited Arrhythmias Database]
==Referenties==
<biblio>
<biblio>
#Schwartz2001 pmid=11136691
#Schwartz2001 pmid=11136691
Line 270: Line 312:
#Roden pmid=18184962
#Roden pmid=18184962
</biblio>
</biblio>
1. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103:89-95.
2. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348:1866-74.
3. 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.
4. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007; 115:2481-9.
5. Alders M, Mannens MAM. Romano-Ward Syndrome. In: Pagon RA, Bird TD, Dolan CR et al. Editors. GeneReviews. PMID 20301308. Seatle (WA).
6. 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.
7. Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124:2181-4.
8. 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.
9. 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.
10. 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.
11. 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.
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