Q-T SyndromesQ-T Syndromes

ByBy

Mahmoud ShahMahmoud ShahProfessor of cardiologyProfessor of cardiology

Zagazig universityZagazig university

Q-T SyndromesQ-T Syndromes►Q-T syndromes can be divided intoQ-T syndromes can be divided into : :

A-A-Long Q-T Syndrome,Long Q-T Syndrome,

B-B-Short Q-T SyndromeShort Q-T Syndrome

►The upper limit for duration of the The upper limit for duration of the normal QT interval corrected for heart normal QT interval corrected for heart rate (QTc) is 0.44 second . However, rate (QTc) is 0.44 second . However, the normal corrected QT interval may the normal corrected QT interval may actually be longer (0.46 second for actually be longer (0.46 second for men and 0.47 second for women), with men and 0.47 second for women), with a normal range of plus or minus 15 a normal range of plus or minus 15 percent of the mean value. percent of the mean value.

►Bazet formulaBazet formula

*QTc=QT/square root of R-R interval*QTc=QT/square root of R-R interval

►The nature of the U wave The nature of the U wave abnormality and its relationship to abnormality and its relationship to long-QT syndrome is not clear. M long-QT syndrome is not clear. M cells may be responsible for the U cells may be responsible for the U wave long-QT syndrome.wave long-QT syndrome.

►The probable risk of life-The probable risk of life-threatening ventricular threatening ventricular arrhythmias developing in patients arrhythmias developing in patients with idiopathic long-QT syndrome with idiopathic long-QT syndrome is related to the length of the QTc is related to the length of the QTc interval. interval.

►T wave “humps” in the ECG can T wave “humps” in the ECG can suggest the presence of long-QT suggest the presence of long-QT syndrome and may be caused by syndrome and may be caused by early after depolarization. A point early after depolarization. A point score system has been suggested score system has been suggested to aid in the diagnosis. Unique T to aid in the diagnosis. Unique T wave contours have been ascribed wave contours have been ascribed to specific genotypes.to specific genotypes.

Long Q-T syndromeLong Q-T syndrome►ECG in long Q-T Syndrome will ECG in long Q-T Syndrome will

show the following:show the following:

1-Prolonged Q-T interval .1-Prolonged Q-T interval .

2-Abnormal morphology of T-wave.2-Abnormal morphology of T-wave.

3-Torsade de points.3-Torsade de points.

►Torsade de points is activated by:Torsade de points is activated by:

1-SNS,1-SNS,

2-Sudden pause.2-Sudden pause.

►LQTS results in :LQTS results in :

-35% of Sudden Cardiac Death in -35% of Sudden Cardiac Death in young,young,

-9% of Sudden infant death -9% of Sudden infant death syndromesyndrome

Congenital LQTSCongenital LQTS►The congenital form is a familial disorder The congenital form is a familial disorder

that can be associated with sensorineural that can be associated with sensorineural deafness (deafness (Jervell and Lange-Nielsen Jervell and Lange-Nielsen syndrome, autosomal recessivesyndrome, autosomal recessive) or,) or,

►Normal hearing (Normal hearing (Romano-Ward Romano-Ward syndrome, autosomal dominantsyndrome, autosomal dominant). ).

►Most forms of congenital long-QT syndrome Most forms of congenital long-QT syndrome are caused by are caused by inherited inherited channelopathieschannelopathies created by mutations in created by mutations in one or more genes.one or more genes.

Genes involved in LQTSGenes involved in LQTS

Variant Gene Variant Gene LQT1 LQT1

KCNQ1KCNQ1

LQT2 LQT2 KCNH2KCNH2

LQT3 LQT3 SCNSASCNSA

LQT4 ANK2LQT4 ANK2

LQT5 LQT5 KCNE1KCNE1

Protein PhenotypeProtein Phenotype

IKs Prolonged IKs Prolonged QTQT

Ikr Prolonged Ikr Prolonged QTQT

INa Prolonged INa Prolonged QTQT

Ankyrin B Prolonged Ankyrin B Prolonged QTQT

Iks Prolonged Iks Prolonged QTQT

Variant GeneVariant Gene

LQT6 KCNE2LQT6 KCNE2

LQT7 KCNJ2LQT7 KCNJ2 (Anderson Syndrome)(Anderson Syndrome)

LQT8 LQT8 ((Timothy Synd.) Timothy Synd.) CANAIcCANAIc

LQT9 CAV3 LQT9 CAV3

LQT10 LQT10 SCN4B SCN4B

Protein PhenotypeProtein Phenotype

Iki Prolonged QT Iki Prolonged QT

IK (IK (Long Q-T and K-sen.preiodic Long Q-T and K-sen.preiodic paralysis)paralysis)

Ca Long Ca Long QT,ASD,PFOQT,ASD,PFO

Prolonged QTProlonged QT

NaB4 Prolonged NaB4 Prolonged QTQT

►The familial long QT syndrome is an The familial long QT syndrome is an uncommon disorder with an uncommon disorder with an estimated prevalence of 1 in 3,000 to estimated prevalence of 1 in 3,000 to 1 in 5,000 .1 in 5,000 .

►It is characterized by a prolonged QT It is characterized by a prolonged QT interval (440 milliseconds in male interval (440 milliseconds in male patient and 460 milliseconds in patient and 460 milliseconds in female patients) associated with T-female patients) associated with T-wave abnormalities and a propensity wave abnormalities and a propensity for polymorphic ventricular for polymorphic ventricular arrhythmias including torsade de arrhythmias including torsade de pointes. pointes.

►Molecular genetic studies have identified Molecular genetic studies have identified mutations in the genes encoding ion mutations in the genes encoding ion channel proteins that control cardiac channel proteins that control cardiac repolarization .repolarization .

► Seven genetic variants have been Seven genetic variants have been identified to date. Most of these mutations identified to date. Most of these mutations result in a loss or reduction in repolarizing result in a loss or reduction in repolarizing currents. An exception is LQT3, which currents. An exception is LQT3, which results in delayed inactivation of the results in delayed inactivation of the sodium channel, leading to longer duration sodium channel, leading to longer duration of depolarizing currents. The final common of depolarizing currents. The final common pathway consists of QT prolongation, pathway consists of QT prolongation, reduced repolarization reserve, and a reduced repolarization reserve, and a predisposition to early after predisposition to early after depolarizations that may trigger depolarizations that may trigger polymorphic VT. polymorphic VT.

► Collectively, these variants account for Collectively, these variants account for only 50% to 70% of patients with long QT only 50% to 70% of patients with long QT syndrome, and mutations in additional syndrome, and mutations in additional genes remain to be identified. Genotype-genes remain to be identified. Genotype-phenotype correlations with respect to phenotype correlations with respect to clinical course and prognosis, clinical course and prognosis, precipitating factors for arrhythmias, ECG precipitating factors for arrhythmias, ECG features, and therapeutic response are features, and therapeutic response are emerging.emerging.

► For example, LQT3 appears to be the most For example, LQT3 appears to be the most

malignant form, and it is the least malignant form, and it is the least responsive to B-blocker therapy, with responsive to B-blocker therapy, with symptoms usually occurring at rest or symptoms usually occurring at rest or sleep without obvious precipitants.sleep without obvious precipitants.

► In contrast, LQT1 typically presents In contrast, LQT1 typically presents with less prolonged QT intervals, a with less prolonged QT intervals, a more favorable long-term prognosis, a more favorable long-term prognosis, a strong association with exercise strong association with exercise provocation (particularly swimming), provocation (particularly swimming), and an excellent response to B-and an excellent response to B-blockersblockers

►The diagnosis of long QT syndrome The diagnosis of long QT syndrome may be straight forward in patients may be straight forward in patients presenting with a clearly prolonged presenting with a clearly prolonged QT interval and syncope. A scoring QT interval and syncope. A scoring system for the diagnosis of long QT system for the diagnosis of long QT syndrome, combining information syndrome, combining information from the ECG, clinical history, and from the ECG, clinical history, and family history, was proposed by family history, was proposed by Schwartz and associates to improve Schwartz and associates to improve the accuracy of diagnosis .the accuracy of diagnosis .

DiagnosisDiagnosis

►At least 10% to 20% of patients At least 10% to 20% of patients with confirmed mutations may with confirmed mutations may have a normal QT interval on have a normal QT interval on initial presentation .Provocative initial presentation .Provocative tests such as epinephrine infusion tests such as epinephrine infusion may be useful in disclosing occult may be useful in disclosing occult long QT syndrome, particularly long QT syndrome, particularly patients with the LQT1 .patients with the LQT1 .

►Genetic testing may be useful if a Genetic testing may be useful if a mutation is identified, but it mutation is identified, but it cannot be used to exclude the cannot be used to exclude the diagnosis if testing reveals no diagnosis if testing reveals no abnormalities. abnormalities.

Diagnostic criteria of congenital Diagnostic criteria of congenital long QT-syndrome long QT-syndrome

►A-ELECTROCARDIOGRAM:A-ELECTROCARDIOGRAM: POINTS POINTS1-QTc >480 ms 31-QTc >480 ms 32-QTc 460-470 22-QTc 460-470 24-450 (male) 14-450 (male) 15-Torsade de pointes 25-Torsade de pointes 26-T-wave alternans 16-T-wave alternans 17-Notched T wave in three leads 17-Notched T wave in three leads 18-Low heart rate for age (less than the 8-Low heart rate for age (less than the

second percentile) second percentile) 0.5 0.5

B-CLINICAL HISTORY:B-CLINICAL HISTORY:

1-Syncope (exclusive of documented 1-Syncope (exclusive of documented torsade)  :torsade)  :

** With stress 2  ** With stress 2  

**Without stress 1**Without stress 1

**Congenital deafness**Congenital deafness 0.5 0.5

C-FAMILY HISTORY:C-FAMILY HISTORY:

1-Family member with definite long QT 1-Family member with definite long QT syndrome 1syndrome 1

2- Unexplained sudden death at <30 y 2- Unexplained sudden death at <30 y in an immediate family member in an immediate family member 0.50.5

InterpretationInterpretation

►>4, definite long QT syndrome;>4, definite long QT syndrome;

► 3-4, possible long QT syndrome, 3-4, possible long QT syndrome,

►<1, low probability of long QT <1, low probability of long QT syndrome. syndrome.

Aquired long QT-SyndromeAquired long QT-Syndrome

► The acquired form has a long-QT interval The acquired form has a long-QT interval caused by various drugs, such as caused by various drugs, such as quinidine, procainamide, N-quinidine, procainamide, N-acetylprocainamide, sotalol, acetylprocainamide, sotalol, amiodarone, disopyramide, amiodarone, disopyramide, phenothiazines, tricyclic phenothiazines, tricyclic antidepressants, erythromycin, antidepressants, erythromycin, pentamidine, some antimalarials, pentamidine, some antimalarials, cisapride, and probucol; electrolyte cisapride, and probucol; electrolyte abnormalities, such as hypokalemia and abnormalities, such as hypokalemia and hypomagnesemia; hypomagnesemia;

► The effects of a liquid protein diet and The effects of a liquid protein diet and starvation; central nervous system starvation; central nervous system lesions; significant bradyarrhythmias; lesions; significant bradyarrhythmias; cardiac ganglionitis; and mitral valve cardiac ganglionitis; and mitral valve prolapse. prolapse.

► In some cases, the acquired long-QT In some cases, the acquired long-QT syndrome may be a form of the inherited syndrome may be a form of the inherited form, resulting from polymorphism in form, resulting from polymorphism in some of the same genes responsible for some of the same genes responsible for the acquired syndrome, which becomes the acquired syndrome, which becomes manifest when a person takes a drug manifest when a person takes a drug impairing repolarization.impairing repolarization.

Management of LQTSManagement of LQTS

Class I:Class I:

1-Life style modification (level of 1-Life style modification (level of evidence B)evidence B)

2-Beta blockers (level of evidence B)2-Beta blockers (level of evidence B)

3-ICD and Beta blockers in:3-ICD and Beta blockers in:

a)Previous cardiac arrest,a)Previous cardiac arrest,

b)Previous syncope,b)Previous syncope,

c)Family history of sudden cardiac death.c)Family history of sudden cardiac death.

Class IIa:Class IIa:

1-Beta blockers decrease incidence of 1-Beta blockers decrease incidence of SCD in molecular LQTS and normal QT SCD in molecular LQTS and normal QT intervalinterval

(level of evidence B).(level of evidence B).

2-ICD and BB decreses incidence of SCD 2-ICD and BB decreses incidence of SCD in LQTS patients with syncope and /or in LQTS patients with syncope and /or VT.AVT.A

Class IIb:Class IIb:

1-Left cardiac sympathetic denervation in:1-Left cardiac sympathetic denervation in:

a)LQTS and syncope,TDP, or, Cardiac a)LQTS and syncope,TDP, or, Cardiac arrestarrest

while receiving BB .while receiving BB .

(level of evidence B)(level of evidence B)

2-ICD and BB as a prophylaxis of SCD for 2-ICD and BB as a prophylaxis of SCD for patients with high risk of cardiac arrest patients with high risk of cardiac arrest (LQT2,LQT3,QTc more than 500 msec).(LQT2,LQT3,QTc more than 500 msec).

(level of evidence B)(level of evidence B)

►Beta-blockers are effective Beta-blockers are effective especially in LQT1 .especially in LQT1 .

►Combined incidence of Combined incidence of resuscitated CA and SCD:resuscitated CA and SCD:

*1% in LQT1,*1% in LQT1,

*7% in LQT2,*7% in LQT2,

*14% in LQT3 *14% in LQT3

*Increased risk of CA , SCD in :*Increased risk of CA , SCD in :

a)Young less than (40 years),a)Young less than (40 years),

b)Asymptomic,b)Asymptomic,

c)Untreated.c)Untreated.

*All LQTS are treated ,except:*All LQTS are treated ,except:

a)Borderline QTc,a)Borderline QTc,

b)LQT1 male more than 25-30 years.b)LQT1 male more than 25-30 years.

*All symptomatic patients must be *All symptomatic patients must be treated.treated.

*Recurrent syncope despite BB:*Recurrent syncope despite BB:

a)Left cardiac sympathetic a)Left cardiac sympathetic denervation (LCSD),denervation (LCSD),

b)Prophylactic ICD.b)Prophylactic ICD.

►Predictors of failure of BB in LQTS:Predictors of failure of BB in LQTS:

1-LQT2,LQT3 genotypes,1-LQT2,LQT3 genotypes,

2-QTc more than 500msec,2-QTc more than 500msec,

3-First syncope less than 7 years,3-First syncope less than 7 years,

*All require ICD as primary *All require ICD as primary prevention prevention

►Indications of permenant pacemaker:Indications of permenant pacemaker:

*Infrequently used today,*Infrequently used today,

*Only in selected LQTS and AV.block ,or *Only in selected LQTS and AV.block ,or sinus block or pause-dependant sinus block or pause-dependant tachycardia ,tachycardia ,

*Adjunt to BB or ICD.*Adjunt to BB or ICD.

**LQT3 :**LQT3 :

*Caused by increased late INa,*Caused by increased late INa,

*Na-channel blockers (mexelitine) *Na-channel blockers (mexelitine) induce short Q-T in LQT3,not LQT2.induce short Q-T in LQT3,not LQT2.

►Mexiletine and BB are effective in Mexiletine and BB are effective in infants with prolonged QT and infants with prolonged QT and major arrhythmias.major arrhythmias.

*Triggers of cardiac events:*Triggers of cardiac events:

-LQT1 :increased risk with physical -LQT1 :increased risk with physical or emotional stress.or emotional stress.

-LQT3 :Increased risk at rest or -LQT3 :Increased risk at rest or during sleep (80%), 5% only during during sleep (80%), 5% only during exerciseexercise

►LQT2: increased risk during:LQT2: increased risk during:

a)Arousla or emotions (37%),a)Arousla or emotions (37%),

b)Sleep ,rest (63%),b)Sleep ,rest (63%),

c)Not at all during exercise.c)Not at all during exercise.

*99% of cardiac events during *99% of cardiac events during swimming LQT1.swimming LQT1.

*80% of events during arousal *80% of events during arousal LQT2.LQT2.

**Symptomatic LQTS :**Symptomatic LQTS :

LQT1 :4% SCD / CA ,LQT1 :4% SCD / CA ,

LQT2 :4% SCD / CA ,LQT2 :4% SCD / CA ,

LQT3 :17% SCD /CA.LQT3 :17% SCD /CA.

*Natural history and risk *Natural history and risk stratification:stratification:

-Lower cummulative event-free -Lower cummulative event-free survival in LQT2 vs LQT1 and LQT3 survival in LQT2 vs LQT1 and LQT3 vs LQT1,vs LQT1,

*Gender :*Gender :

-no influence among LQT1,-no influence among LQT1,

- Females are at higher risk in LQT2,- Females are at higher risk in LQT2,

-Males are at a higher risk in LQT3,-Males are at a higher risk in LQT3,

*Silent mutation carriers *Silent mutation carriers (genetically affected patients with (genetically affected patients with normal QT- interval:normal QT- interval:

-More in LQT1(36%) than in LQT2 -More in LQT1(36%) than in LQT2 (19%) ,LQT3 (10%).(19%) ,LQT3 (10%).

1-1-Higher risk Higher risk (SCD / CA /Syncope):(SCD / CA /Syncope):

-50% risk ,-50% risk ,

-QTc more than 500msec,-QTc more than 500msec,

-LQT1, LQT2, male LQT3.-LQT1, LQT2, male LQT3.

2-Intermediate risk:2-Intermediate risk:

-30-50% risk,-30-50% risk,

-QTc less than 500msec,-QTc less than 500msec,

-Female LQT2,-Female LQT2,

-Male LQT3,-Male LQT3,

-QTc 500 in female with LQT3.-QTc 500 in female with LQT3.

3-Low3-Low riskrisk::

-Risk less than 30%,-Risk less than 30%,

-QTc less than 500 msec,-QTc less than 500 msec,

-Male LQT2,-Male LQT2,

-LQT1-LQT1

ECG in long QT-syndromeECG in long QT-syndrome

ECG of a patient with long Q-T (0,54 s) due to ECG of a patient with long Q-T (0,54 s) due to hypokalemia caused by excessive diuretic hypokalemia caused by excessive diuretic

therapy.therapy.

Long Q-T syndrome Long Q-T syndrome progressed to TDPprogressed to TDP

TDPTDP

Short QT-SyndromeShort QT-Syndrome

A heritable cardiac ion channel A heritable cardiac ion channel disorder disorder

associated with a high risk of associated with a high risk of recurrent recurrent

syncope, polymorphic VT, and syncope, polymorphic VT, and sudden death sudden death

has been identified recently in has been identified recently in several families. several families.

DiagnosisDiagnosis

►ECG shows:ECG shows:• Q-T interval more than 300msec,Q-T interval more than 300msec,• Distinct T-wave shape,Distinct T-wave shape,• Absent ST-segment.Absent ST-segment.►Clinical :Clinical :

-Silent mutation carriers rather -Silent mutation carriers rather prevelant in LQT6 not present in prevelant in LQT6 not present in SQTS.SQTS.

-It is due to impaired Q-T -It is due to impaired Q-T adaptation to increased heart adaptation to increased heart rate.rate.

-Q-T measured at heart rate less -Q-T measured at heart rate less than 80 bpm.than 80 bpm.

-It is difficult to identify SQTS in -It is difficult to identify SQTS in infants and very young children.infants and very young children.

► Mutations in the genes Mutations in the genes contributing to at least three contributing to at least three different repolarizing currents have different repolarizing currents have been identified: IKr (KCNH2), IKs been identified: IKr (KCNH2), IKs (KCNQ1), and IK1 (KCNJ2).(KCNQ1), and IK1 (KCNJ2).

► All these mutations result in gain All these mutations result in gain of function, thus accelerating of function, thus accelerating repolarization and accounting for repolarization and accounting for the clinical features of the disease.the clinical features of the disease.

Secondary causes of SQTSSecondary causes of SQTS

►Hypercalcaemia,Hypercalcaemia,►Hyperkalemia,Hyperkalemia,►Hyperthermia,Hyperthermia,►Acidosis,Acidosis,►Digoxin therapy.Digoxin therapy.

►The most cardinal clinical The most cardinal clinical manifestations include atrial and manifestations include atrial and ventricular fast rhythm (AF , VF).ventricular fast rhythm (AF , VF).

►Suspected SQTS in :Suspected SQTS in :

-Short Q-T interval (less than 350msec)-Short Q-T interval (less than 350msec)

-Lone AF or primary VF.-Lone AF or primary VF.

-Family history of SCD ,CA ,SIDS , -Family history of SCD ,CA ,SIDS , syncope.syncope.

-One of the channelopathies results in -One of the channelopathies results in SIDS.SIDS.

►ICDs are the most effective ICDs are the most effective therapy, although the frequent therapy, although the frequent coexistence of atrial fibrillation coexistence of atrial fibrillation and prominent T waves that and prominent T waves that results in oversensing may results in oversensing may increase the risk of inappropriate increase the risk of inappropriate shocks in these patients.shocks in these patients.

Management of SQTSManagement of SQTS

►High risk for SCD.High risk for SCD.►Lack of drugs in preventing SCD.Lack of drugs in preventing SCD.►ICD for secondary prevention of VF.ICD for secondary prevention of VF.►ICD in selected patients for primary ICD in selected patients for primary

prevention of VF.prevention of VF.

**No risk stratification parameters **No risk stratification parameters that identify patient with high risk of that identify patient with high risk of SCDSCD

►Antiarrhthmic drugs for SQTS are Antiarrhthmic drugs for SQTS are progressing and may be used as a progressing and may be used as a bridge to ICD.bridge to ICD.

►Sotalol ,Ibutilide ,Flecanide proved Sotalol ,Ibutilide ,Flecanide proved ineffective.ineffective.

►Quinidine normalizes QT interval at Quinidine normalizes QT interval at resting HR in small number of resting HR in small number of patients resulting in prolonged patients resulting in prolonged ventricular effective refractory ventricular effective refractory period.period.

►