LQTS: Difference between revisions

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<i>Supervisor: Arthur A.M. Wilde</i>
<i>Supervisor: Arthur A.M. Wilde</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.


[[Image:De-Formule QTc.png|right|thumb|Formula for heart rate corrected QT interval (Bazett’s formula)]]
[[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  
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.  
occurs in a patient with congenital LQTS.  


==Diagnosis==
==Diagnosis==
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*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 genotyped LQTS patients) a QTc > 430ms makes it likely that a LQTS gene defect is present.
*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  
*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.
 
stratification.


===Physical examination===
===Physical examination===
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==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  
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.  
 
increase.  
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==Congenital LQTS==
==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  
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.  
 
relatively common.  


The three most common forms of LQTS can be recognized by the characteristic clinical features and ECG abnormalities  
The three most common forms of LQTS can be recognized by the characteristic clinical features and ECG abnormalities  
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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 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.  
 
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.<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  
*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).
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).


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==Clinical diagnosis==
==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  
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.  
 
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.  
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.]]
[[Image:LQTS_triggers.svg|thumb|right|400px|Various triggers for cardiac events have been identified among the different genotypes.]]
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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 above in the  
*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.
 
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.  
 
*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.
characteristic T-wave abnormalities.  
*Epinephrine infusion is a provocative test that might increase the sensitivity of the ECG findings. However, especially the negative predictive value is high.  
*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  
*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>
 
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.]]
[[Image:Lqts1-3.png|thumb|right|400px|Various triggers for cardiac events have been identified among the different genotypes.]]


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==Genetic diagnosis==
==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  
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.  
 
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.
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.


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==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  
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.
 
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==
==Treatment==
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===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  
*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 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.  
found, but no QT prolongation is visible on the ECG and also in LQTS3 patients with bradycardia-associated cardiac events <cite>congenital</cite>
*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.  
*[[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.