Heart, Lung and Circulation (2016) 25, 769–776 POSITION STATEMENT 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2016.01.020 Update on the Diagnosis and Management of Familial Long QT Syndrome Kathryn E Waddell-Smith, FRACP a,b, Jonathan R Skinner, FRACP, FCSANZ, FHRS, MD a,b*, members of the CSANZ Genetics Council Writing Group aGreen Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland New Zealand bDepartment[5_TD$IF] of Paediatrics,[6_TD$IF] Child[7_TD$IF] and[8_TD$IF] Youth[9_TD$IF] Health,[10_TD$IF] University of Auckland, Auckland, New Zealand Received 17 December 2015; accepted 20 January 2016; online published-ahead-of-print 5 March 2016 This update was reviewed by the CSANZ Continuing Education and Recertification Committee and ratified by the CSANZ board in August 2015. Since the CSANZ 2011 guidelines, adjunctive clinical tests have proven useful in the diagnosis of LQTS and are discussed in this update. Understanding of the diagnostic and risk stratifying role of LQTS genetics is also discussed. At least 14 LQTS genes are now thought to be responsible for the disease. High-risk individuals may have multiple mutations, large gene rearrangements, C-loop mutations in KCNQ1, transmembrane mutations in KCNH2, or have certain gene modifiers present, particularly NOS1AP polymorphisms. In regards to treatment, nadolol is preferred, particularly for long QT type 2, and short acting metoprolol should not be used. Thoracoscopic left cardiac sympathectomy is valuable in those who cannot adhere to beta blocker therapy, particularly in long QT type 1. Indications for ICD therapies have been refined; and a primary indication for ICD in post-pubertal females with long QT type 2 and a very long QT interval is emerging. Keywords Long QT syndrome Diagnosis Management Genetics Sudden death Clinical Characteristics High risk individuals are identified by QTc500ms and/or syncope in the previous two years. Boys and post Summary Overview pubertal females (especially in the nine post-partum months) are high risk. Long QT syndrome (LQTS) is a familial condition causing Risk reduction is achieved through lifestyle modification, syncope and sudden death through polymorphic ventric- avoidance of QT prolonging drugs, beta blockade and less ular tachycardia (torsades de pointes), which can deterio- commonly with left cardiac sympathetic denervation or rate to ventricular fibrillation, in otherwise fit and healthy ICD insertion. young people. Prevalence is approximately 1 in 2,500 [1]. Changes from Previous 2011 Document Clinical diagnosis is made from a combination of suspi- An expanded section is included on QTc analysis, see text. cious clinical history (sudden unheralded syncope or car- Since 2011, adjunctive clinical tests have proven useful in the diac arrest typically associated with exercise, stress, startle diagnosis of LQTS. At four minutes after cessation of an or during sleep) and family history, and the 12 lead ECG. exercise test, a QTc exceeding 480ms is highly suggestive ECG typically reveals a heart-rate corrected QT interval of LQTS and is reflected in the Schwarz criteria. Likewise, (QT/HR-R interval = QTc) repeatedly greater than 470ms QTc assessment at 10 seconds after standing shows a greater in women and 450ms in men, in the absence of other prolongation in those affected by LQTS when compared with known factors prolonging the QT interval. unaffected individuals. *Corresponding author at: Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Private Bag 92024, Auckland 1142, New Zealand. Tel.: +64 9 3074949; fax: +64 9 6310785, Email: [email protected] © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved. 770 K.E. Waddell-Smith, J.R. Skinner Understanding of the diagnostic and risk stratifying role of ventricular tachycardia) until proven otherwise. Misdiag- LQTS genetics is discussed. At least 14 LQTS genes are now nosis of LQTS as epilepsy, particularly ‘‘familial epilepsy’’, thought to be responsible for the disease. High-risk individ- is common [5]. Seizures during exertion or arousal, and uals may have multiple mutations, large gene rearrange- during sleep, must raise the suspicion of LQTS. ments, C-loop mutations in KCNQ1, transmembrane Differentiation from neurocardiogenic syncope is usually mutations in KCNH2, or have certain gene modifiers present. made on history. Neurocardiogenic syncope typically fol- In regards to treatment, nadolol is preferred and short acting lows pain or prolonged upright posture, has a long prodrome metoprolol should not be used. Indications for ICD therapy and is associated with nausea [6]. Ambulatory event moni- are refined to (1) resuscitated cardiac arrest (2) recurrent toring or implantable loop recorder can be valuable in detect- arrhythmic syncope whilst adherent to beta blockers, see text ing or excluding arrhythmia at time of syncope if other tests for relative indications. An emerging primary indication is are inconclusive. A family history of sudden unexplained post pubertal women with long QT type 2 and a QTc >550ms. death in young people is highly suggestive [6]. Studies of the three most common genotypes (Types 1, 2 Clinical Diagnosis and 3) have shown that the life-threatening cardiac events The diagnosis is usually made on clinical grounds, see Table 1, (syncope or sudden death) tend to occur under specific [2,3] and is suggested if the presentation is with syncope circumstances in a gene-specific manner and have character- or resuscitated sudden cardiac death, particularly if associ- istic T wave morphologies [7], see Table 3. Subjects with long ated with exercise, sudden emotional stress, loud noise, QT types 1 and 2 tend to have several ‘‘warning’’ syncopal or when supine. Prodromal symptoms of pre-syncope, episodes before a sudden death, whereas in long QT3 the first palpitations or a change in temperature can be experienced presentation is typically sudden death [8]. [4]. Syncope associated with swimming should be suspected to be LQTS (or CPVT; catecholaminergic polymorphic Electrocardiographic Diagnosis Abnormal ventricular repolarisation is demonstrated through QT prolongation or abnormal T-wave morphology on an incidental ECG or during family screening following a Table 1 Diagnostic Criteria for LQTS (Schwartz Score) sudden unexplained death [9,10]. QT prolongation due to Points drugs or biochemical imbalance (low potassium, calcium or magnesium), hypothermia and myocardial disease must be # Electrocardiographic findings excluded. A QTc^[3_TD$IF] Despite the failings of the Bazett heart-rate correction for- 480 ms 3 mula (QT divided by square root of preceding R-R interval), 460-479 ms 2 it is still in popular use. The end of the QT interval is deter- 450-459 ms (in males) 1 mined by extrapolating the steepest curve of the T wave B QTc^ 4th minute of recovery 1 down to the baseline [11]. Take the longest measurement from exercise stress test 480 ms of lead II or V5 [12]. Individuals with LQTS can have a C Torsade de pointes* 2 normal QTc and vice versa [13,14]. Heart Rhythm Society D T wave alternans 1 guidelines suggest that, outside of family cascade screening, E Notched T wave in 3 leads 1 in asymptomatic individuals a QTc of 500ms on two F Low heart rate for age@ 0.5 separate ECGs is required to make the diagnosis of LQTS, Clinical History but in patients with unexplained syncope, the diagnosis can A Syncope* be made from QTc 480 ms on repeated ECGs [15]. With stress 2 Holter recordings are of limited additional value for mak- Without stress 1 ing the diagnosis unless torsades de pointes or T-wave alter- B Congenital deafness 0.5 nans is documented (which is very rare), or there is a history Family History suggesting nocturnal events. A Family members with definite LQTS$ 1 Exercise testing can be helpful. In the recovery phase fol- B Unexplained sudden cardiac 0.5 lowing exercise, QT intervals of LQTS mutation carriers and death age 30 among immediate non-carriers tend to separate more than at rest. An absolute QT family members$ interval of over 0.37 sec at a heart-rate of 100 post exercise is highly suggestive of LQTS types 1 or 2; a QT below 0.34 sec #In the absence of medications or disorders known to affect these electro- makes it unlikely [16]. QTc prolongation at four mins post cardiographic features; ^QTc calculated by Bazett’s formula where exercise >480ms gains 1 Schwartz score point [17,18]. Norma- H [4_TD$IF] QTc=QT/ RR; *Mutually exclusive; @Resting heart-rate below the 2nd tive values for children are available [19]. percentile for age; $The same family member cannot be counted in A Examination of QT interval in the moments after standing and B. can indicate LQTS carriage [20]. With the patient supine Score: 1 point: low probability of LQTs; 1.5 to 3 points: intermediate probability of LQTS; 3.5 points high probability. and 12-lead ECG monitoring, the patient briskly stands and within 10 secs, heart-rate[4_TD$IF] increases (i.e. RR interval Q1 Update on the Diagnosis and Management of Familial Long QT Syndrome 771 decreases). In those affected by LQTS, the QT interval Therefore, examining T-wave morphology, reviewing QT reduces much less than the RR interval (there is less than interval behaviour after exercise testing and performing a 20ms change in absolute QT). Therefore, at maximal QT genetic testing are important adjuvants. The length of stretch (where the end of the T-wave is closest to the next P- the QT interval is linked to the risk of syncope and sudden wave (i.e. the RR has shortened without the QTc adapting death, but all gene carriers are at an increased risk, and and shortening)) the QTc increases by 89Æ47ms and ventric- have 50% chance of passing on the mutation to each of their ular ectopic beats or T-wave alternans may be seen.