LQTS: Difference between revisions

Jump to navigation Jump to search
3,645 bytes added ,  25 March 2013
m
no edit summary
 
mNo edit summary
 
(27 intermediate revisions by 3 users not shown)
Line 1: Line 1:
[[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.]]
<i>Auteur: Louise R.A. Olde Nordkamp</i>
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.
<i>Supervisor: Arthur A.M. Wilde</i>


===Diagnosis===
[[Image:De-Formule QTc.png|right|thumb|Formula for heart rate corrected QT interval (Bazett’s formula)]]
*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]].
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.
*Sometimes the QT interval can be difficult to assess. Read the [[Difficult_QT|guidelines for measurement of difficult QT interval]].
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.  
*A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk for 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>
*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>


===Treatment<cite>ACC2006</cite>===
==Diagnosis==
*"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===
===General===
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 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 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 (without additional QT-prologing factors) for risk stratification.


{|  
===Physical examination===
[[Image:Torsade_de_Pointes.png|500px|right|thumb]]
Patients can present with symptoms of arrhythmias:
*Fast or slow heart beat
*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.
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
|-
|-
|valign="top"|
!
{| class="wikitable" width="400px"
===Notorious QT prolonging drugs:===
!Common drugs that can cause [[Torsade_de_Pointes|Torsade de Pointes]] include:<cite>Roden</cite>
|-
|-
|
|
<ul>
#Amiodarone
<li>Sotalol</li>
#Chloroquine
<li>Amiodarone</li>
#Chlorpromazine
<li>Erythromycin</li>
#Citalopram
<li>Clarithromycin</li>
#Claritromycin
</ul>
#Disopyramide
#Dofetilide
#Erythromycin
#Flecainide
#Halofantrine
#Haloperidol
#Quinidine
#Sotalol
 
|}
 
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
|-
|-
!Less often used drugs include:
!
===Concomittant risk factors for medication induced torsade de pointes:===
|-
|-
|
|
<ul>
#Female sex
<li>Cisapride</li>
#Hypokalemia
<li>antibiotics: halofantrine, pentamidine, sparfloxacin</li>
#Bradycardia
<li>Anti-emetics: domperidon, droperidol</li>
#Recent conversion of atrial fibrillation, especially if QT prolonging drugs were used (sotalol, amiodarone)
<li>Anti-psychotics: chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide</li>
#Cardiac decompensation
<li>Methadon</li>
#Digoxin treatment
<li>Disopyramide</li>
#High or overdosing or rapid infusion of a QT prolonging drug
<li>Dofetilide</li>
#Pre-existing QT prolongation
<li>Ibutilide</li>
#Congenital QT syndrome
<li>Procainamide</li>
 
<li>Quinidine</li>
<li>Bepridil</li>
</ul>
|-
|[http://www.torsades.org Torsades.org] has an extensive list of drugs that can TdP
|}
|valign="top"|
{| class="wikitable" align="right" width="400px"
!Concomittant risk factors for medication induced [[Torsade_de_Pointes|Torsade de Pointes]]:
|-
|
<ul>
<li>Female sex</li>
<li>Hypokalemia</li>
<li>Bradycardia</li>
<li>Recent conversion of [[Atrial Fibrillation|atrial fibrillation]], especially if QT prolonging drugs were used (sotalol, amiodarone)</li>
<li>Cardiac decompensation</li>
<li>Digoxin treatment</li>
<li>High or overdosing or rapid infusion of a QT prolonging drug</li>
<li>Pre-existing QT prolongation</li>
<li>Congenital long QT syndrome</li>
</ul>
|}
|-
|}
|}


===Congenital LQTS===
[[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
*LQT2 small late T wave
*LQT3 prolonged QT interval with 'late onset' T wave with a normal configuration
In congenital LQTS the ventricular repolarisation is prolonged. '''The prevalence 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>
==Congenital LQTS==
 
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


{| border="1" cellpadding="2" cellspacing="0" bordercolor="#6EB4EB" style="font-size:100%;" class="plainlinks" class="wikitable"
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
|- style="text-align:center;background-color:#6EB4EB;"
|-
| '''Type'''
!LQTS type
| '''Chromosome'''
!LQTS 1
| '''Gene'''
!LQTS 2
| '''Protein'''
!LQTS 3
| '''Ionchannel'''
|-
| '''Frequency<cite>priori</cite>'''
|'''Gene/current'''
| '''SCD incidence<cite>Shah2005</cite>'''
|KCNQ1/IK<sub>s</sub>
| '''Inheritance'''
|KCNH2/IK<sub>r</sub>
| '''ECG characteristics'''
|SCN5A/INa
| '''Trigger'''
|-
| '''Eponyme'''
|'''B-blokker efficacy'''
| '''[[w:OMIM|OMIM&trade;]] link'''
| ++++
| +++
| ++
|-
|'''ECG'''
|''Early onset'' broad based T wave
|Small late T wave
|''Late onset'' T wave with normal configuration
|-
|'''Arrhythmogenic triggers'''
|Exercise, especially swimming
|Adrenergic triggers, especially nightly noise
|Rest
|-
|'''Number of mutation carriers with events at age <15'''
|40%
|20%
|10%
|-
|-
! LQTS1
|'''Number of mutation carriers with events at age <40'''
| 11p15
|60%
| KCNQ1
|60%
| KvLQT1
|50%
| 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
|'''Sudden cardiac death incidence Eponyme'''
| 7q35
|0,30% / year
| KCNH2
|0,60% / year
| hERG
|0,56% / year
| 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
|'''Eponyme'''
| 3p21
|If condition is homozygous: Jervell and Lange-Nielsen syndrome 1
| SCN5A
| NA channel
|
|
| 5-10%
| 0.56%/year
| AD
| 'Late onset' T wave with normal configuration
|
|
|
|}
| {{OMIM2|600163}}
 
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 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 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 a single mutation in the CACNA1C gene (LQTS type 8).
 
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width=""600px"
|-
|-
! LQTS4
|'''Findings'''
| 4q25-q27
| ANK2
| Ankyrin B
| I''Na,K''
| <1%
|
| AD
|
|
|
|
|'''Points'''
|-
|'''ECG'''
|QTc:
|>480 ms
460-479
450-459 (in males)
>480 during X-ECG
|valign="top"|3
2
1
1
|-
|
|
| {{OMIM2|106410}}
|colspan="2"|Torsade de pointes
 
T-wave alternans
 
Notched T-wave in 3 leads
 
Low heart rate for age (<2<sup>nd</sup> percentile for age)
|2
 
1
 
1
 
0.5
|-
|-
! LQTS5
| 21q22.1
| KCNE1
| minK
| I''ks''
| <1%
| unknown
| AD/AR
|
|
|
|Syncope:
|
|With stress
| {{OMIM2|176261}}
Without stress
|2
1
|-
|'''Clinical history'''
|colspan="2"|Congenital deafness
Family members with definite LQTS
|0.5
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''
|}
Diagnostic criteria by Schwartz et al. (2011)<cite>Schwartz2001</cite>
 
==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 events. On the other hand, in LQTS type 3, QT prolongation and possibly subsequent torsade de pointes is precipitated by bradycardia.
 
[[Image:LQTS_triggers.svg|thumb|right|400px|Various triggers for cardiac events have been identified among the different genotypes.]]
 
==ECG tests==
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 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
*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 <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 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.]]
 
 
==Genetic diagnosis==
 
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"
|-
!LQTS type
!Gene
!Protein (Ionchannel)
!OMIM-link
|-
|Type 1
|KCNQ1
|KVLQT1 (I<sub>Ks<sub>)
|607542
|-
|Type 2
|KCNH2
|HERG (I<sub>Kr</sub>)
|613688
|-
|Type 3
|SCN5A
|Sodium channel (I<sub>Na</sub>)
|603830
|-
|Type 4
|ANK2
|Ankyrin B (I<sub>Na, K</sub>)
|600919
|-
|Type 5
|KCNE1
|minK (I<sub>Ks</sub>)
|176261
|-
|Type 6
|KCNE2
|MiRP1 (I<sub>Kr</sub>)
|613693
|-
|Type 7
|KCNJ2
|Kir 2.1 (I<sub>K1</sub>)
|170390
|-
|Type 8
|CACNA1C
|Ca<sub>v</sub>1.2 (I<sub>Ca-L</sub>)
|601005
|-
|-
! LQTS6
|Type 9
| 21q22.1
|CAV3
| KCNE2
|Caveolin-3
| MiRP1
|601253
| I''kr''
| <1%
| unknown
| AD
|
|
|
| {{OMIM2|603796}}
|-
|-
! LQTS7 = ATS1
|Type 10
| 17q23
|SCN4B
| KCNJ2
|Sodium channel (I<sub>Na</sub>)
| Kir 2.1
|608256
| I''K1''
| <1%
| unknown
| AD
|
|
| Anderson-Tawil syndrome
| {{OMIM2|600681}}
|-
|-
! LQTS8 = TS1
|Type 11
| 12p13.3
|AKAP9
| CACNA1C
|A-Kinase anchor 9 (I<sub>Ks</sub>)
| Ca<sub>v</sub>1.2
|604001
| I''Ca-L''
| <1%
| unknown
|
| alternating T waves
|
| Timothy syndrome
| {{OMIM2|601005}}
|-
|-
! LQTS9
|Type 12
| 3p25.3
|SNTA1
| CAV3
|Syntrophin (I<sub>Na</sub>)
| Caveolin 3
|601017
| I''Na''
|
| unknown
|
|
|
|
| {{OMIM2|601253}}
|-
|-
! LQTS10
|Type 13
| 11q23.3
|KCNJ5
| SCN4B
|Kir3.4 (I<sub>K</sub>)
| Na<sub>v</sub>1.5 b4
|600734
|
| 1 family
| unknown
|
|
|
|
| {{OMIM2|608256}}
|-
|-
! LQTS11
|Type 14
| 7q21-q22
|CALM1
| Akap9
|Calmodulin 1
| AKAP
|114180
| I''ks''
| 1 family
| unknown
|
|
|
|
| {{OMIM2|611820}}
|}
|}
;LQTS: Long QT syndrome
;JLN: Jervell and Lange-Nielsen syndrome
;SCD: Sudden Cardiac Death
Long before the genes involved were known, two syndromes  associated with a prolonged QT interval on the ECG had been described.
* 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==
==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==
 
==="Lifestyle modification":===
*Probably no competitive sports in all LQTS patients
*Avoid QT-prolonging drugs in all LQTS patients
*No swimming or diving  in LQT1 patients
*Avoid nightly or sudden 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 prolon
 
 
==References==
<biblio>
<biblio>
#Schwartz2001 pmid=11136691
#Schwartz2001 pmid=11136691
#Shah2005 pmid=16230503
#Alders pmid=20301308
#Lang1957 pmid=13435203
#adenosine pmid=16105845
#ACC2006 pmid=16935995
#Goldenberg pmid=16949500
#Roden pmid=14999113
#moss pmid=17470695
#priori pmid=12736279
#priori pmid=12736279
#Hofman pmid=17090615
#Adler pmid=22300664
#Roden pmid=18184962
#Shimizu2009 pmid=19926013
#Moss pmid=17470695
#Sy pmid=22042885
#Schwartz2011 pmid=22083145
#Viskin pmid=20116193
#Shimizu2004 pmid=15851169
</biblio>
</biblio>

Navigation menu