Long QT Syndrome

Author(s)	J.S.S.G. de Jong, MD
Moderator	P.G. Postema, MD
Supervisor
some notes about authorship

The Long QT Syndrome (LQTS) is characterized on the ECG by prolongation of the heart rate corrected QT interval. 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.[1]

The Long QT syndrome may be divided into two distinct forms: congenital Long QT syndrome and acquired Long QT syndrome. These forms may however overlap when QT prolongation due to medication occurs in a patient with congenital Long QT syndrome.

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  A 12-lead ECG of a patient with acquired long QT syndrome. Notice the QT prolongation. The QTc is about 640ms.

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  A 12 lead ECG of a patient with genetically proven LQTS1

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  A 12 lead ECG of a patient with genetically proven LQTS2

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  A 12 lead ECG of a patient with genetically proven LQTS3

Diagnosis

• 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.
• A QTc of > 500ms in patients with Long QT Syndrome is associated with an increased risk for sudden death.[2]
• In patients suspected of LQTS (e.g. family members of known LQTS patients) a QTc > 430ms makes it likely that a LQTS gene defect is present.[3]
• Because the QTc can change with age, it is best to take the ECG with the longest QTc interval for risk stratification.[4]

Treatment[5]

• "Lifestyle modification":
  • No competitive sports in all LQTS patients
  • No swimming in LQT1 patients
  • Avoid nightly noise in LQT2 patients (e.g. no alarm clock)
• Medication: beta-blockers. Beta-blockers even reduce the risk of sudden death in patients in whom a genetic defect has been found, but no QT prolongation is visible on the ECG.
• ICD implantation in combination with beta-blockers in LQTS patients with previous cardiac arrest or syncope or ventricular tachycardia while on beta-blockers.

Acquired LQTS

Acquired LQTS is most often caused by drugs that prolong the QT interval. Combined with risk factors (see table) the risk of Torsade de Pointes increases.

Common drugs that can cause Torsade de Pointes include:[6] Sotalol Amiodarone Erythromycin Clarithromycin Less often used drugs include: Cisapride antibiotics: halofantrine, pentamidine, sparfloxacin Anti-emetics: domperidon, droperidol Anti-psychotics: chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide Methadon Disopyramide Dofetilide Ibutilide Procainamide Quinidine Bepridil Torsades.org has an extensive list of drugs that can TdP

Concomittant risk factors for medication induced Torsade de Pointes: Female sex Hypokalemia Bradycardia Recent conversion of atrial fibrillation, especially if QT prolonging drugs were used (sotalol, amiodarone) Cardiac decompensation Digoxin treatment High or overdosing or rapid infusion of a QT prolonging drug Pre-existing QT prolongation Congenital long QT syndrome

Congenital LQTS

The three most common forms of LQTS can be recognized by the characteristic ECG abnormalities

:

• LQT1 'early onset' broad based T wave
• LQT2 small late T wave
• LQT3 prolonged QT interval with 'late onset' T wave with a normal configuration

In congenital LQTS the ventricular repolarisation is prolonged. The prevalence is about 1:3000-5000.

More than 10 different types of congenital LQTS have been described. However, only LQTS 1-3 are relatively common.[5]

Type	Chromosome	Gene	Protein	Ionchannel	Frequency[7]	SCD incidence[8]	Inheritance	ECG characteristics	Trigger	Eponyme	OMIM™ link
LQTS1	11p15	KCNQ1	KvLQT1	Iks	~50%	0.30%/year	AD, AR	broad base 'early onset' T wave	exercise, especially swimming	JLN1 if homozygous, LQTS1 if heterozygous	607542
LQTS2	7q35	KCNH2	hERG	Ikr	30-40%	0.60%/year	AD	small late T wave	adrenergic triggers, especially nightly noise	JLN2 if homozygous, LQTS2 if heterozygous	152427
LQTS3	3p21	SCN5A	NA channel		5-10%	0.56%/year	AD	'Late onset' T wave with normal configuration			600163
LQTS4	4q25-q27	ANK2	Ankyrin B	INa,K	<1%		AD				106410
LQTS5	21q22.1	KCNE1	minK	Iks	<1%	unknown	AD/AR				176261
LQTS6	21q22.1	KCNE2	MiRP1	Ikr	<1%	unknown	AD				603796
LQTS7 = ATS1	17q23	KCNJ2	Kir 2.1	IK1	<1%	unknown	AD			Anderson-Tawil syndrome	600681
LQTS8 = TS1	12p13.3	CACNA1C	Cav1.2	ICa-L	<1%	unknown		alternating T waves		Timothy syndrome	601005
LQTS9	3p25.3	CAV3	Caveolin 3	INa		unknown					601253
LQTS10	11q23.3	SCN4B	Nav1.5 b4		1 family	unknown					608256
LQTS11	7q21-q22	Akap9	AKAP	Iks	1 family	unknown					611820

LQTS

Long QT syndrome

JLN

Jervell and Lange-Nielsen syndrome

SCD

Sudden Cardiac Death

Long before the genes involved were known, two syndromes associated with a prolonged QT interval on the ECG had been described.

• Anton Jervell and Fred Lange-Nielsen from Oslo described in 1957 an autosomaal recessive syndrome that was associated with QT interval prolongation, deafness and sudden death: the now called Jervell-Lange-Nielsen syndrome. [1]
• Romano-Ward syndrome is a long QT syndrome with normal auditory function and autosomal dominant inheritance.
• In a genotype–phenotype study by Moss et al. that studied type-1 LQTS, it was found that mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.[9]

External links

1. Torsades.org has a list of QT prolonging drugs
2. QTdrugs.org, another list of QT prolonging drugs
3. Sudden Arrhythmia Death Syndrome Foundation. LQTS patient group.
4. Inherited Arrhythmias Database

Referenties

1. JERVELL A and LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957 Jul;54(1):59-68. DOI:10.1016/0002-8703(57)90079-0 |
3. Hofman N, Wilde AA, Kääb S, van Langen IM, Tanck MW, Mannens MM, Hinterseer M, Beckmann BM, and Tan HL. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?. Eur Heart J. 2007 Mar;28(5):575-80. DOI:10.1093/eurheartj/ehl355 |
4. Goldenberg I, Mathew J, Moss AJ, McNitt S, Peterson DR, Zareba W, Benhorin J, Zhang L, Vincent GM, Andrews ML, Robinson JL, and Morray B. Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification. J Am Coll Cardiol. 2006 Sep 5;48(5):1047-52. DOI:10.1016/j.jacc.2006.06.033 |
5. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, American College of Cardiology/American Heart Association Task Force, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, and Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5;114(10):e385-484. DOI:10.1161/CIRCULATIONAHA.106.178233 |
6. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med. 2008 Jan 10;358(2):169-76. DOI:10.1056/NEJMcp0706513 |
6. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004 Mar 4;350(10):1013-22. DOI:10.1056/NEJMra032426 |
7. 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 |
8. Shah M, Akar FG, and Tomaselli GF. Molecular basis of arrhythmias. Circulation. 2005 Oct 18;112(16):2517-29. DOI:10.1161/CIRCULATIONAHA.104.494476 |
9. 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 |
10. 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 |