7/4/23, 12:19 AM LQTS - Textbook of Cardiology LQTS Auteur: Louise R.A. Olde Nordkamp Supervisor: Arthur A.M. Wilde 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. File:De-Formule QTc.png Formula for heart rate corrected QT interval (Bazett s formula) Contents Diagnosis General Physical examination Acquired LQTS Notorious QT prolonging drugs: Concomittant risk factors for medication induced torsade de pointes: Congenital LQTS Clinical diagnosis ECG tests Genetic diagnosis Risk Stratification Treatment "Lifestyle modification": Medication/Other therapies: References Diagnosis General The diagnosis is by measurement of the heart rate corrected QT interval on the ECG, which can be calculated with the QTc calculator. Sometimes the QT interval can be difficult to assess. Read the guidelines for measurement of difficult QT interval. https://www.textbookofcardiology.org/wiki/LQTS 1/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk of torsade de pointes and sudden death.[1] 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 stratification. Physical examination Patients can present with symptoms of arrhythmias: Fast or slow heart beat Weakness, lightheadedness, dizziness, syncope Chest pain Shortness of breath Paleness Sweating Acquired LQTS https://www.textbookofcardiology.org/wiki/LQTS 2/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology 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. Notorious QT prolonging drugs: 1. Amiodarone 2. Chloroquine 3. Chlorpromazine 4. Citalopram 5. Claritromycin 6. Disopyramide 7. Dofetilide 8. Erythromycin 9. Flecainide 10. Halofantrine 11. Haloperidol 12. Quinidine 13. Sotalol Concomittant risk factors for medication induced torsade de pointes: 1. Female sex 2. Hypokalemia 3. Bradycardia 4. Recent conversion of atrial fibrillation, especially if QT prolonging drugs were used (sotalol, amiodarone) 5. Cardiac decompensation 6. Digoxin treatment 7. High or overdosing or rapid infusion of a QT prolonging drug 8. Pre-existing QT prolongation 9. Congenital QT syndrome 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 relatively common. The three most common forms of LQTS can be recognized by the characteristic clinical features and ECG abnormalities https://www.textbookofcardiology.org/wiki/LQTS 3/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology LQTS type LQTS 1 LQTS 2 LQTS 3 KCNQ1/IKs KCNH2/IKr Gene/current SCN5A/INa B-blokker efficacy ++++ +++ ++ Late onset T wave with normal configuration Early onset broad based T wave ECG Small late T wave Adrenergic triggers, especially nightly noise Arrhythmogenic triggers Exercise, especially swimming Rest Number of mutation carriers with events at age <15 40% 20% 10% Number of mutation carriers with events at age <40 60% 60% 50% Sudden cardiac death incidence Eponyme 0,30% / year 0,60% / year 0,56% / year If condition is homozygous: Jervell and Lange-Nielsen syndrome 1 Eponyme 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 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.[2] 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). https://www.textbookofcardiology.org/wiki/LQTS 4/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology Findings Points >480 ms 3 460-479 2 ECG QTc: 450-459 (in males) 1 >480 during X-ECG 1 Torsade de pointes 2 T-wave alternans 1 Notched T-wave in 3 leads 1 Low heart rate for age (<2nd percentile for age) 0.5 With stress 2 Syncope: Without stress 1 Congenital deafness 0.5 Clinical history Family members with definite LQTS 1 Family history Unexplained sudden cardiac death before age 30 0.5 Total score 1 Low probability; 1.5-3 Intermediate probability; 3.5 High probability Diagnostic criteria by Schwartz et al. (2011)[3] 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 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. ECG tests ECGs can be difficult because there is a considerable overlap between the QT interval of affected and unaffected individuals. https://www.textbookofcardiology.org/wiki/LQTS 5/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology 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. 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 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 [4] 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[5] Various triggers for cardiac events have been identified among the different genotypes. Genetic diagnosis Today, 14 LQTS genes associated with LQTS have 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. been Various triggers for cardiac events have been identified among the different genotypes. There is an important genotype-phenotype relationship on severity of the disease.[3] 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. https://www.textbookofcardiology.org/wiki/LQTS 6/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology LQTS type Gene Protein (Ionchannel) OMIM-link KVLQT1 (IKs) Type 1 KCNQ1 607542 HERG (IKr) Type 2 KCNH2 613688 Sodium channel (INa) Type 3 SCN5A 603830 Ankyrin B (INa, K) Type 4 ANK2 600919 minK (IKs) Type 5 KCNE1 176261 MiRP1 (IKr) Type 6 KCNE2 613693 Kir 2.1 (IK1) Type 7 KCNJ2 170390 Cav1.2 (ICa-L) Type 8 CACNA1C 601005 Type 9 CAV3 Caveolin-3 601253 Sodium channel (INa) Type 10 SCN4B 608256 A-Kinase anchor 9 (IKs) Type 11 AKAP9 604001 Syntrophin (INa) Type 12 SNTA1 601017 Kir3.4 (IK) Type 13 KCNJ5 600734 Type 14 CALM1 Calmodulin 1 114180 Risk Stratification 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. Treatment "Lifestyle modification": Probably no competitive sports in all LQTS patients Avoid QT-prolonging drugs in all LQTS patients No swimming or diving in LQT1 patients https://www.textbookofcardiology.org/wiki/LQTS 7/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology Avoid nightly or sudden noise in LQT2 patients (e.g. no alarm clock) 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 found, but no QT prolon References 1. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, and Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003 May 8;348(19):1866-74. DOI:10.1056/NEJMoa022147 | 2. Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Alders M, Bikker H, and Christiaans I. Long QT Syndrome. 1993. 3. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, and Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 2;103(1):89- 95. DOI:10.1161/01.cir.103.1.89 | 4. Adler A, van der Werf C, Postema PG, Rosso R, Bhuiyan ZA, Kalman JM, Vohra JK, Guevara- Valdivia ME, Marquez MF, Halkin A, Benhorin J, Antzelevitch C, Wilde AA, and Viskin S. The phenomenon of "QT stunning": the abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome. Heart Rhythm. 2012 Jun;9(6):901-8. DOI:10.1016/j.hrthm.2012.01.026 | 5. Viskin S, Rosso R, Rogowski O, Belhassen B, Levitas A, Wagshal A, Katz A, Fourey D, Zeltser D, Oliva A, Pollevick GD, Antzelevitch C, and Rozovski U. Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome. Eur Heart J. 2006 Feb;27(4):469-75. DOI:10.1093/eurheartj/ehi460 | 6. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, and McNitt S. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54(22):2052-62. DOI:10.1016/j.jacc.2009.08.028 | 7. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, and McNitt S. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007 May 15;115(19):2481-9. DOI:10.1161/CIRCULATIONAHA.106.665406 | 8. Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde AA, and Krahn AD. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011 Nov 15;124(20):2187-94. DOI:10.1161/CIRCULATIONAHA.111.028258 | 9. Schwartz PJ and Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011 Nov 15;124(20):2181-4. DOI:10.1161/CIRCULATIONAHA.111.062182 | 10. Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Kogan E, Belhassen B, Glikson M, Strasberg B, Antzelevitch C, and Wilde AA. The response of https://www.textbookofcardiology.org/wiki/LQTS 8/9 7/4/23, 12:19 AM LQTS - Textbook of Cardiology the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome. J Am Coll Cardiol. 2010 May 4;55(18):1955-61. DOI:10.1016/j.jacc.2009.12.015 | 11. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K, Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K, Ohe T, Towbin JA, Priori SG, and Kamakura S. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm. 2004 Sep;1(3):276-83. DOI:10.1016/j.hrthm.2004.04.021 | Retrieved from "http://www.textbookofcardiology.org/index.php?title=LQTS&oldid=2283" This page was last edited on 25 March 2013, at 21:14. Content is available under Attribution-NonCommercial-ShareAlike 3.0 Unported unless otherwise noted. https://www.textbookofcardiology.org/wiki/LQTS 9/9