Long QT syndrome Done by: Dr. Ayman Bukhari Dr. Amin Zagzoog Supervised by: Dr. Mona Kholeif Consultant Cardiologist

Introduction Long QT syndrome (LQTS) is a disorder characterized by a prolongation of the QT interval on ECG and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. The Bazett formula is used to calculate the QTc, as follows: QTc = QT/square root of the R-R interval.

Definition of QTc Based on Age- and Sex-Specific Criteria GroupProlongedBorderlineReference Children and adolescents (<15 y) > <0.44 Men> <0.43 Women> <0.45

Introduction This uncommon disease was first described in 1957 in family in which several children with QT prolongation, congenital bilateral neural deafness, and syncopal episodes, with a family pattern suggesting autosomal-recessive inheritance (Jervell and Lange-Nielsen syndrome ). Romano ward syndrome has autosomal dominant pattern. The LQTS can be congenital, as an inherited disorder usually involving a mutation of an ion channel gene, or can be acquired as an adverse response to medication, metabolic abnormalities, or bradyarrhythmias Torsade de pointes (TdP) or "twisting of points" is the specific type of polymorphic ventricular tachycardia (VT) associated with either form of the LQTS.

Torsades de pointes

Prevalance The prevalence of LQTS is difficult to estimate. However, given the currently increasing frequency of diagnosis, LQTS may be expected to occur in 1 in 10,000 individuals. New cases of long QT syndrome are diagnosed more in female patients (60-70% of cases) than male patients. The female predominance may be related to the relatively prolonged QTc (as determined by using the Bazett formula) No clear evidence suggests race-related differences in the occurrence of long QT syndrome. LQT1, LQT2, and LQT3 account for most cases of LQTS, with estimated prevalences of 45%, 45%, and 7%, respectively

Pathophysiology Acquired : -polymorphic VT is most commonly precipitated by a characteristic sequence of long-short RR intervals. This interval is normally caused by a ventricular premature beat followed by a compensatory pause. Polymorphic VT can similarly occur in association with bradycardia or frequent pauses; as a result, the acquired form of LQTS is called "pause-dependent" LQTS. Congenital: - TdP typically follows a sudden adrenergic surge. Such patients are considered to have "catecholamine- dependent" LQTS

Torsade de pointes The electrocardiographic rhythm strip shows torsade de pointes, a polymorphic ventricular tachycardia associated with QT prolongation. There is a short, preinitiating RR interval due to a ventricular couplet which is followed by a long, initiating cycle resulting from the compensatory pause after the couplet.

Pathophysiology Representation of an action potential in ventricular myocardial cells. An action potential is generated when the membrane potential is partially depolarized from the resting level (Em) to the threshold potential (Et). The ensuing rapid phase 0 depolarization is mediated by sodium entry into the cells due to a marked increase in the number of open sodium channels in the cell membrane. Repolarization in phases 1 and 3 results from potassium exit from the cells as the sodium channels are closed and potassium channels opened. The phase 2 plateau reflects the slow entry of calcium into the cells, which counteracts the effect of potassium exit. Sodium leaves and potassium reenters the cells during phase 4 recovery via the Na-K-ATPase pump

Pathophysiology 1)Prolonged repolarization and EADs Prolongation of the QT interval may be associated with the presence of early after depolarizations (EADs). EADs are single or multiple oscillations of the membrane potential that can occur during phase 2 or 3 of the action potential. EADs occur in association with prolongation of the repolarization phase of the action potential. The development of EADs is potentiated by bradycardia, hypokalemia, hypomagnesemia and a long list of medications.

Early Afterdepolarization and staff.com

Signal averaged Electrocardiogram

Pathophysiology 2) Increased sympathetic activity Evidence supporting the significance of sympathetic activity in LQTS includes observations on the impact of the stellate ganglia. The activity of the left sympathetic stellate ganglion is greater than that of the right ganglion in normal individuals. In addition, the left stellate ganglion innervates the majority of the ventricle. Increased activity of the left stellate ganglion or reduced activity of the right stellate ganglion leads to increased sympathetic innervation of the heart. Studies in both animals and humans have demonstrated that right stellectomy or stimulation of the left stellate ganglion both prolong the QTinterval and alter T wave morphology in a manner that mimics the surfaceECG found in patients with LQTS.

Genetic Type of Long QT syndrome Chromosomal Locus Mutated Gene Ion Current Affected LQT1 (Romano ward Syndrome) 11p15.5 KVLQT1, or KCNQ1 (heterozygotes) Potassium (I Ks ) LQT27q35-36HERG, KCNH2Potassium (I Kr ) LQT33p21-24SCN5ASodium (I Na ) LQT44q25-27ANK2, ANKB Sodium, potassium and calcium LQT521q KCNE1 (heterozygotes) Potassium (I Ks ) LQT621q MiRP1, KNCE2Potassium (I Kr ) LQT7 (Anderson syndrome) 17q23.1-q24.2KCNJ2Potassium (I K1 )

Genetic Type of Long QT syndrome Type of LQTS Chromosomal Locus Mutated Gene Ion Current Affected LQT8 (Timothy syndrome) 12q13.3CACNA1CCalcium (I Ca-Lalpha ) LQT93p25.3CAV3Sodium (I Na ) LQT1011q23.3SCN4BSodium (I Na ) LQT117q21-q22AKAP9Potassium (I Ks ) LQT12 SNTAISodium (I Na ) JLN111p15.5 KVLQT1, or KCNQ1 (homozygotes) Potassium (I Ks ) JLN221q KCNE1 (homozygotes) Potassium (I Ks )

Drugs That Prolong QT 1)Anti-arrhythmic: 4) Anti-psychotic -Amiodarone -Chlorpromazine -Disopyramide -Haloperidol -Dofetilide -Ziprasidone 2)Antibiotics: -Olanzpine -Levofloxacin 5) Diuretics -Erythromycin -Indapamide -Gatifloxacin 6)Anti histamine -Clarithromycin 3) Anti-depressant 7) Anti-cancer -Fluoxetine -Tamoxifen -Paroxetine -Arsenic trioxide

History Long QT syndrome (LQTS) is usually diagnosed after a person has a cardiac event (eg, syncope, cardiac arrest). In some situations, LQTS is diagnosed after a family member suddenly dies. In some individuals, LQTS is diagnosed because an ECG shows QT prolongation. A history of cardiac events is the most typical clinical presentation in patients with LQTS. – LQT1 :usually have cardiac events preceded by exercise or swimming. Sudden exposure of the patient's face to cold water is thought to elicit a vagotonic reflex. – LQT2: may have arrhythmic events after an emotional event, exercise, or exposure to auditory stimuli (eg, door bells, telephone ring) – LQT3: usually have events during night sleep. Obtain information about hearing loss (deficit) in a patient and his or her family members to determine a possibility of Jervell and Lang-Nielsen (JLN) syndrome.

History Medication Family history Analysis of repolarization duration (QTc) and morphology on the patient's ECG and on ECGs of the patient's relatives frequently leads to the proper diagnosis.

Physical Examination Findings on physical examination usually do not indicate a diagnosis of long QT syndrome (LQTS) excessive bradycardia for their age hearing loss (congenital deafness), indicating the possibility of JLNsyndrome Skeletal abnormalities, such as short stature and scoliosis are seen in LQT7 (Andersen syndrome) congenital heart diseases, cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction may be seen in those with LQT8 (Timothy syndrome).

Physical Examination Also perform the physical examination to exclude other potential reasons for arrhythmic and syncopal events in otherwise healthy people (e.g, heart murmurs caused by hypertrophic cardiomyopathy, valvular defects).

Diagnostic criteria for long QT syndrome CriterionPoints ECG Finding QTc > in male patient 1 Torsade de pointes‡2 T-wave alternans1 Notched T wave in 3 leads1 Low heart rate for age§0.5 Clinical history Syncope With stress2 Without stress1 Congenital deafness0.5 Family history A. Family members with definite LQTS#1 B. Unexplained sudden cardiac death <30 y in an immediate family member0.5

Investigation 1)Laboratory Studies -Serum potassium - Serum magnesium - Thyroid function Test -Genetic Testing 2) Imaging Studies -Echocardiography -MRI

Investigation 3)ECG -LQTS patients frequently show abnormal T-wave morphology, and careful evaluation of all 12 leads is recommended to determine the presence or absence of even subtle changes in T-wave shape. This is particularly important and useful in patients with QTc durations in thegray zone of s, where the diagnosis is uncertain based on just QTc. -Individuals with QTc < 0.5s are frequently referred for exercise ECG testing, 24- hour Holter monitoring, or sometimes event monitoring. The diagnostic value of these modalities in borderline cases is still controversial 4)Electrophysiological studies

T-wave morphology by LQTS genotype: LQT1: typical broad-based T-wave pattern (corrected QT [QTc] 570 ms); LQT2: typical bifid T-wave (QTc 583 ms); and LQT3: typical late-onset peaked/biphasic T-wave (QTc 573 ms

Marked prolongation of QT interval in a 15-year-old male adolescent with long QT syndrome (LQTS) (R-R = 1.00 s, QT interval = 0.56 s, QT interval corrected for heart rate [QTc] = 0.56 s). Abnormal morphology of repolarization can be observed in almost every lead (ie, peaked T waves, bowing ST segment). Bradycardia is a common feature in patients with LQTS.

Managament Direct current shock non synchrnoized Discontinuation of the offending agent Any offending agent should be withdrawn. Predisposing conditions such as hypokalemia, hypomagnesaemia, and bradycardia should be identified and corrected Suppression of early after depolarizations Magnesium is the drug of choice for suppressing EADs and terminating the arrhythmia. This is achieved by decreasing the influx of calcium, thus lowering the amplitude of EADs. Isoproterenol This drug can be used in bradycardia-dependent torsade that usually associated with acquired long QT syndrome (pause-dependent). Temporary transvenous pacing

Managament 1)Beta-blockers The protective effect of beta-blockers is related to their adrenergic blockade that diminishes the risk of cardiac arrhythmias. They may also reduce the QT interval in some patients. Propranolol and nadolol are the beta-blockers most frequently used, though atenolol and metoprolol are also prescribed in patients with LQTS. 2)Implantable Cardioverter-defibrillator (ICD) It was shown to be highly effective to prevent sudden cardiac death (SCD) in high- risk patients i.e patient with syncopal attack

Managment 3) Left cervicothoracic stellectomy  Although this technique decreases the risk of cardiac events, it does not eliminate the risk. Therefore, ICD is superior therapy to cervicothoracic stellectomy.

Suggested Risk-Stratification Scheme for ACA or SCD in LQTS Patients Ilan Goldenberg, MD, Arthur J. Moss, MD Rochester, New York, American Journal of Cardiology 2008

Managament ElectrocardiogramSymptomsFamily historyTreatment Prolong QTNone Prolong QTNoneSCD, Syncope due to LQTS Beta-blockers Prolong QTSyncope SCD, Syncope due to LQTSBeta-blockers, ICD Prolong QTSCDBeta-blockers, ICD

Probability of LQTS-Related Events by Gender Kaplan-Meier estimates of the cumulative probability of (A) a first cardiac event (syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) and (B) a first life-threatening cardiac event (ACA or SCD) from age 1 through 75 years by gender in 3,779 long QT syndrome (LQTS) patients from the International LQTS Registry

Classification of Cardiomyopathy

Summary -Prevalence -Types -Drugs -ECG

References 1)Essential Cardiac Electrophysiology Zainul Abedin and Robert Conner 2)Long QT syndrome Ali A Sovari, MD, Research Fellow, Division of Cardiology, David Geffen School of Medicine,University of California, Los Angeles (UCLA) Abraham G Kocheril, MD, FACC, FACP, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago; Ramin Assadi, MD, Staff Physician, Department of Internal Medicine, Loma Linda University

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