Difference between revisions of "LQTS"

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<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>
  
 +
[[Image:De-Formule QTc.png|right|thumb|Formula for heart rate corrected QT interval (Bazett’s formula)]]
 +
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.
 
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 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===
 +
[[Image:Torsade_de_Pointes.png|500px|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
Line 25: Line 27:
  
 
==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"
===Notorious QT prolonging drugs: <cite>Roden</cite>===
+
|-
 +
!
 +
===Notorious QT prolonging drugs:===
 +
|-
 +
|
 
#Amiodarone
 
#Amiodarone
#Azithromycin
 
 
#Chloroquine
 
#Chloroquine
 
#Chlorpromazine
 
#Chlorpromazine
Line 40: Line 46:
 
#Halofantrine
 
#Halofantrine
 
#Haloperidol
 
#Haloperidol
#Procainamide
 
 
#Quinidine
 
#Quinidine
 
#Sotalol
 
#Sotalol
  
 +
|}
 +
 +
{| class="wikitable" border="0" cellspacing="0" cellpadding="0" width="400px"
 +
|-
 +
!
 
===Concomittant risk factors for medication induced torsade de pointes:===
 
===Concomittant risk factors for medication induced torsade de pointes:===
 +
|-
 +
|
 
#Female sex
 
#Female sex
 
#Hypokalemia
 
#Hypokalemia
Line 54: Line 66:
 
#Pre-existing QT prolongation
 
#Pre-existing QT prolongation
 
#Congenital QT syndrome
 
#Congenital QT syndrome
 +
 +
|}
 +
  
 
==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="100%"
+
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
 
|-
 
|-
 
!LQTS type
 
!LQTS type
Line 74: Line 90:
 
|'''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'''
Line 88: Line 102:
 
|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
Line 100: Line 119:
 
|-
 
|-
 
|'''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 sudden death: the now called Jervell-Lange-Nielsen syndrome.  
*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.  
+
*Romano-Ward syndrome is a long QT syndrome with normal auditory function and autosomal dominant inheritance.<cite>Alders</cite>
 
 
*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).
 
*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).
  
*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).
+
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width=""600px"
 
 
===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%"
 
|-
 
!colspan="4"|Diagnostic criteria by Schwartz et al.
 
 
|-
 
|-
 
|'''Findings'''
 
|'''Findings'''
Line 135: Line 143:
 
460-479
 
460-479
  
450-459
+
450-459 (in males)
  
>480 during  
+
>480 during X-ECG
 
 
X-ECG
 
 
|valign="top"|3
 
|valign="top"|3
  
Line 181: Line 187:
 
|0.5
 
|0.5
 
|-
 
|-
|colspan="4"|''Total score =1 Low probability; 1.5-3 Intermediate probability; =3.5 High probability''
+
|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>
  
[[Image:LQTS_triggers.svg|thumb|400px|Various triggers for cardiac events have been identified among the different genotypes.]]
+
==Clinical diagnosis==
  
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.
+
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.  
  
===ECG tests===
+
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:Lqts1-3.png|right|thumb|400px|Various ECG patterns can be recognized among the different genotypes]]
 
  
 +
[[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.
 
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 characteristic T-wave abnormalities.  
 
*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.]]
  
*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.
 
  
*Epinephrine infusion is a provocative test that increases the sensitivity of the ECG findings
+
==Genetic diagnosis==
  
*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
+
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.
  
==Genetic diagnosis==
+
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.
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.  
 
  
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="100%"
+
{| class="wikitable" border="1" cellpadding="1" cellspacing="1" width="600px"
 
|-
 
|-
 
!LQTS type
 
!LQTS type
Line 279: Line 288:
 
|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.
 
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>==
+
==Treatment==
===Lifestyle modification===  
+
 
*No competitive sports in all LQTS patients  
+
==="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
+
*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
  
*[[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.
 
 
 
==References==
 
==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
#Roden1 pmid=18184962
+
#Shimizu2009 pmid=19926013
#Alders pmid=20301308
+
#Moss pmid=17470695
#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.
+
#Sy 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.
+
#Schwartz2011 pmid=22083145
#Schwartz Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124:2181-4.
+
#Viskin 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.
+
#Shimizu2004 pmid=15851169
#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.
 
#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.
 
#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.
 
 
</biblio>
 
</biblio>

Latest revision as of 21:14, 25 March 2013

Auteur: Louise R.A. Olde Nordkamp

Supervisor: Arthur A.M. Wilde

File:De-Formule QTc.png
Formula for heart rate corrected QT interval (Bazett’s formula)

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. 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

General

  • 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.[1]
  • 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

Torsade de Pointes.png

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.

Notorious QT prolonging drugs:

  1. Amiodarone
  2. Chloroquine
  3. Chlorpromazine
  4. Citalopram
  5. Claritromycin
  6. Disopyramide
  7. Dofetilide
  8. Erythromycin
  9. Flecainide
  10. Halofantrine
  11. Haloperidol
  12. Quinidine
  13. Sotalol

Concomittant risk factors for medication induced torsade de pointes:

  1. Female sex
  2. Hypokalemia
  3. Bradycardia
  4. Recent conversion of atrial fibrillation, especially if QT prolonging drugs were used (sotalol, amiodarone)
  5. Cardiac decompensation
  6. Digoxin treatment
  7. High or overdosing or rapid infusion of a QT prolonging drug
  8. Pre-existing QT prolongation
  9. Congenital QT syndrome


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

LQTS type LQTS 1 LQTS 2 LQTS 3
Gene/current KCNQ1/IKs KCNH2/IKr SCN5A/INa
B-blokker efficacy ++++ +++ ++
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%
Number of mutation carriers with events at age <40 60% 60% 50%
Sudden cardiac death incidence Eponyme 0,30% / year 0,60% / year 0,56% / year
Eponyme If condition is homozygous: Jervell and Lange-Nielsen syndrome 1

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.[2]
  • 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).
Findings Points
ECG QTc: >480 ms

460-479

450-459 (in males)

>480 during X-ECG

3

2

1

1

Torsade de pointes

T-wave alternans

Notched T-wave in 3 leads

Low heart rate for age (<2nd percentile for age)

2

1

1

0.5

Syncope: With stress

Without stress

2

1

Clinical history Congenital deafness

Family members with definite LQTS

0.5

1

Family history Unexplained sudden cardiac death before age 30 0.5
Total score ≤1 Low probability; 1.5-3 Intermediate probability; ≥3.5 High probability

Diagnostic criteria by Schwartz et al. (2011)[3]

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.

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 [4] 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[5]
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.[3] 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.

LQTS type Gene Protein (Ionchannel) OMIM-link
Type 1 KCNQ1 KVLQT1 (IKs) 607542
Type 2 KCNH2 HERG (IKr) 613688
Type 3 SCN5A Sodium channel (INa) 603830
Type 4 ANK2 Ankyrin B (INa, K) 600919
Type 5 KCNE1 minK (IKs) 176261
Type 6 KCNE2 MiRP1 (IKr) 613693
Type 7 KCNJ2 Kir 2.1 (IK1) 170390
Type 8 CACNA1C Cav1.2 (ICa-L) 601005
Type 9 CAV3 Caveolin-3 601253
Type 10 SCN4B Sodium channel (INa) 608256
Type 11 AKAP9 A-Kinase anchor 9 (IKs) 604001
Type 12 SNTA1 Syntrophin (INa) 601017
Type 13 KCNJ5 Kir3.4 (IK) 600734
Type 14 CALM1 Calmodulin 1 114180


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

  1. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, and Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348(19):1866-74. DOI:10.1056/NEJMoa022147 | PubMed ID:12736279 | HubMed [priori]
  2. Alders M, Bikker H, Christiaans I, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, and Amemiya A. Long QT Syndrome. 1993. PubMed ID:20301308 | HubMed [Alders]
  3. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, and Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 2;103(1):89-95. PubMed ID:11136691 | HubMed [Schwartz2001]
  4. Adler A, van der Werf C, Postema PG, Rosso R, Bhuiyan ZA, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Halkin A, Benhorin J, Antzelevitch C, Wilde AA, and Viskin S. 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 Jun;9(6):901-8. DOI:10.1016/j.hrthm.2012.01.026 | PubMed ID:22300664 | HubMed [Adler]
  5. Viskin S, Rosso R, Rogowski O, Belhassen B, Levitas A, Wagshal A, Katz A, Fourey D, Zeltser D, Oliva A, Pollevick GD, Antzelevitch C, and Rozovski U. 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 Feb;27(4):469-75. DOI:10.1093/eurheartj/ehi460 | PubMed ID:16105845 | HubMed [adenosine]
  6. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, and McNitt S. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54(22):2052-62. DOI:10.1016/j.jacc.2009.08.028 | PubMed ID:19926013 | HubMed [Shimizu2009]
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  8. Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde AA, and Krahn AD. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011 Nov 15;124(20):2187-94. DOI:10.1161/CIRCULATIONAHA.111.028258 | PubMed ID:22042885 | HubMed [Sy]
  9. Schwartz PJ and Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011 Nov 15;124(20):2181-4. DOI:10.1161/CIRCULATIONAHA.111.062182 | PubMed ID:22083145 | HubMed [Schwartz2011]
  10. Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Kogan E, Belhassen B, Glikson M, Strasberg B, Antzelevitch C, and Wilde AA. 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 May 4;55(18):1955-61. DOI:10.1016/j.jacc.2009.12.015 | PubMed ID:20116193 | HubMed [Viskin]
  11. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K, Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K, Ohe T, Towbin JA, Priori SG, and Kamakura S. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm. 2004 Sep;1(3):276-83. DOI:10.1016/j.hrthm.2004.04.021 | PubMed ID:15851169 | HubMed [Shimizu2004]

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