By Mahmoud Shah Professor of cardiology Zagazig university Q-T Syndromes By Mahmoud Shah Professor of cardiology Zagazig university

Q-T Syndromes Q-T syndromes can be divided into : A-Long Q-T Syndrome, B-Short Q-T Syndrome

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

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

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

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

Long Q-T syndrome ECG in long Q-T Syndrome will show the following: 1-Prolonged Q-T interval . 2-Abnormal morphology of T-wave. 3-Torsade de points.

Torsade de points is activated by: 1-SNS, 2-Sudden pause. LQTS results in : -35% of Sudden Cardiac Death in young, -9% of Sudden infant death syndrome

Congenital LQTS The congenital form is a familial disorder that can be associated with sensorineural deafness (Jervell and Lange-Nielsen syndrome, autosomal recessive) or, Normal hearing (Romano-Ward syndrome, autosomal dominant). Most forms of congenital long-QT syndrome are caused by inherited channelopathies created by mutations in one or more genes.

Genes involved in LQTS Variant Gene Protein Phenotype LQT1 KCNQ1 LQT2 KCNH2 LQT3 SCNSA LQT4 ANK2 LQT5 KCNE1 IKs Prolonged QT Ikr Prolonged QT INa Prolonged QT Ankyrin B Prolonged QT Iks Prolonged QT

Variant Gene Protein Phenotype LQT6 KCNE2 LQT7 KCNJ2 (Anderson Syndrome) LQT8 (Timothy Synd.) CANAIc LQT9 CAV3 LQT10 SCN4B Iki Prolonged QT IK (Long Q-T and K-sen.preiodic paralysis) Ca Long QT,ASD,PFO Prolonged QT NaB4 Prolonged QT

The familial long QT syndrome is an uncommon disorder with an estimated prevalence of 1 in 3,000 to 1 in 5,000 . It is characterized by a prolonged QT interval (440 milliseconds in male patient and 460 milliseconds in female patients) associated with T-wave abnormalities and a propensity for polymorphic ventricular arrhythmias including torsade de pointes.

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

Collectively, these variants account for only 50% to 70% of patients with long QT syndrome, and mutations in additional genes remain to be identified. Genotype-phenotype correlations with respect to clinical course and prognosis, precipitating factors for arrhythmias, ECG features, and therapeutic response are emerging. For example, LQT3 appears to be the most malignant form, and it is the least responsive to B-blocker therapy, with symptoms usually occurring at rest or sleep without obvious precipitants.

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

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

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

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

Diagnostic criteria of congenital long QT-syndrome A-ELECTROCARDIOGRAM: POINTS 1-QTc >480 ms 3 2-QTc 460-470 2 4-450 (male) 1 5-Torsade de pointes 2 6-T-wave alternans 1 7-Notched T wave in three leads 1 8-Low heart rate for age (less than the second percentile) 0.5

B-CLINICAL HISTORY: 1-Syncope (exclusive of documented torsade)  : ** With stress 2   **Without stress 1 **Congenital deafness 0.5

C-FAMILY HISTORY: 1-Family member with definite long QT syndrome 1 2- Unexplained sudden death at <30 y in an immediate family member 0.5

Interpretation >4, definite long QT syndrome; 3-4, possible long QT syndrome, <1, low probability of long QT syndrome.

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

The effects of a liquid protein diet and starvation; central nervous system lesions; significant bradyarrhythmias; cardiac ganglionitis; and mitral valve prolapse. In some cases, the acquired long-QT syndrome may be a form of the inherited form, resulting from polymorphism in some of the same genes responsible for the acquired syndrome, which becomes manifest when a person takes a drug impairing repolarization.

Management of LQTS Class I: 1-Life style modification (level of evidence B) 2-Beta blockers (level of evidence B) 3-ICD and Beta blockers in: a)Previous cardiac arrest, b)Previous syncope, c)Family history of sudden cardiac death.

Class IIa: 1-Beta blockers decrease incidence of SCD in molecular LQTS and normal QT interval (level of evidence B). 2-ICD and BB decreses incidence of SCD in LQTS patients with syncope and /or VT.A

Class IIb: 1-Left cardiac sympathetic denervation in: a)LQTS and syncope,TDP, or, Cardiac arrest while receiving BB . (level of evidence B) 2-ICD and BB as a prophylaxis of SCD for patients with high risk of cardiac arrest (LQT2,LQT3,QTc more than 500 msec).

Beta-blockers are effective especially in LQT1 . Combined incidence of resuscitated CA and SCD: *1% in LQT1, *7% in LQT2, *14% in LQT3

*Increased risk of CA , SCD in : a)Young less than (40 years), b)Asymptomic, c)Untreated.

*All LQTS are treated ,except: a)Borderline QTc, b)LQT1 male more than 25-30 years. *All symptomatic patients must be treated. *Recurrent syncope despite BB: a)Left cardiac sympathetic denervation (LCSD), b)Prophylactic ICD.

Predictors of failure of BB in LQTS: 1-LQT2,LQT3 genotypes, 2-QTc more than 500msec, 3-First syncope less than 7 years, *All require ICD as primary prevention

Indications of permenant pacemaker: *Infrequently used today, *Only in selected LQTS and AV.block ,or sinus block or pause-dependant tachycardia , *Adjunt to BB or ICD. **LQT3 : *Caused by increased late INa, *Na-channel blockers (mexelitine) induce short Q-T in LQT3,not LQT2.

Mexiletine and BB are effective in infants with prolonged QT and major arrhythmias. *Triggers of cardiac events: -LQT1 :increased risk with physical or emotional stress. -LQT3 :Increased risk at rest or during sleep (80%), 5% only during exercise

LQT2: increased risk during: a)Arousla or emotions (37%), b)Sleep ,rest (63%), c)Not at all during exercise. *99% of cardiac events during swimming LQT1. *80% of events during arousal LQT2.

**Symptomatic LQTS : LQT1 :4% SCD / CA , LQT2 :4% SCD / CA , LQT3 :17% SCD /CA. *Natural history and risk stratification: -Lower cummulative event-free survival in LQT2 vs LQT1 and LQT3 vs LQT1,

*Gender : -no influence among LQT1, - Females are at higher risk in LQT2, -Males are at a higher risk in LQT3, *Silent mutation carriers (genetically affected patients with normal QT- interval: -More in LQT1(36%) than in LQT2 (19%) ,LQT3 (10%).

1-Higher risk (SCD / CA /Syncope): -50% risk , -QTc more than 500msec, -LQT1, LQT2, male LQT3. 2-Intermediate risk: -30-50% risk, -QTc less than 500msec, -Female LQT2, -Male LQT3, -QTc 500 in female with LQT3.

3-Low risk: -Risk less than 30%, -QTc less than 500 msec, -Male LQT2, -LQT1

ECG in long QT-syndrome

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

Long Q-T syndrome progressed to TDP

TDP

Short QT-Syndrome A heritable cardiac ion channel disorder associated with a high risk of recurrent syncope, polymorphic VT, and sudden death has been identified recently in several families.

Diagnosis ECG shows: Q-T interval more than 300msec, Distinct T-wave shape, Absent ST-segment. Clinical : -Silent mutation carriers rather prevelant in LQT6 not present in SQTS.

-It is due to impaired Q-T adaptation to increased heart rate -It is due to impaired Q-T adaptation to increased heart rate. -Q-T measured at heart rate less than 80 bpm. -It is difficult to identify SQTS in infants and very young children.

Mutations in the genes contributing to at least three different repolarizing currents have been identified: IKr (KCNH2), IKs (KCNQ1), and IK1 (KCNJ2). All these mutations result in gain of function, thus accelerating repolarization and accounting for the clinical features of the disease.

Secondary causes of SQTS Hypercalcaemia, Hyperkalemia, Hyperthermia, Acidosis, Digoxin therapy.

The most cardinal clinical manifestations include atrial and ventricular fast rhythm (AF , VF). Suspected SQTS in : -Short Q-T interval (less than 350msec) -Lone AF or primary VF. -Family history of SCD ,CA ,SIDS , syncope. -One of the channelopathies results in SIDS.

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

Management of SQTS High risk for SCD. Lack of drugs in preventing SCD. ICD for secondary prevention of VF. ICD in selected patients for primary prevention of VF. **No risk stratification parameters that identify patient with high risk of SCD

Antiarrhthmic drugs for SQTS are progressing and may be used as a bridge to ICD. Sotalol ,Ibutilide ,Flecanide proved ineffective. Quinidine normalizes QT interval at resting HR in small number of patients resulting in prolonged ventricular effective refractory period.

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