Long QT syndrome: Difference between revisions

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	Long QT syndrome;
	Schematic representation of normal ECG trace (sinus rhythm), with waves, segments, and intervals labeled.
ICD-10	I45.8
ICD-9	426.82
DiseasesDB	11104
MeSH	D008133

VisualWikitext

Revision as of 04:58, 24 August 2012

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [3]

Associated syndromes

A number of syndromes are associated with LQTS.

Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes

In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.

Romano-Ward syndrome

Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness.

Mechanism of arrhythmia generation

All forms of the long QT syndrome involve an abnormal repolarization of the heart. The abnormal repolarization causes differences in the "refractoriness" of the myocytes. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias.

It is believed that the so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium channels during the plateau phase of the cardiac action potential. Since adrenergic stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (ie exercise, excitement) -- especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise.

The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca²⁺ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca²⁺ release during repolarization, causing the released Ca²⁺ to exit the cell through the 3Na⁺/Ca²⁺-exchanger which results in a net depolarizing current.

Diagnosis

The diagnosis of LQTS is not easy since 2.5% of the healthy population have prolonged QT interval, and 10% of LQTS patients have a normal QT interval. A commonly used criterion to diagnose LQTS is the LQTS "diagnostic score" ^[1]. Its based on several criteria giving points to each. With 4 or more points the probability is high for LQTS, and with 1 or less point the probability is low. Two or 3 points indicates intermediate probability.

QTc (Defined as QT interval / square root of RR interval)
- >= 480 msec - 3 points
- 460-470 msec - 2 points
- 450 msec and male gender - 1 point
Torsades de Pointes ventricular tachycardia - 2 points
T wave alternans - 1 point
Notched T wave in at least 3 leads - 1 point
Low heart rate for age (children) - 0.5 points
Syncope (one cannot receive points both for syncope and Torsades de pointes)
- With stress - 2 points
- Without stress - 1 point
Congenital deafness - 0.5 points
Family history (the same family member cannot be counted for LQTS and sudden death)
- Other family members with definite LQTS - 1 point
- Sudden death in immediate family (members before the age 30) - 0.5 points

Treatment options

There are two treatment options in individuals with LQTS: arrhythmia prevention, and arrhythmia termination.

Arrhythmia prevention

Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is after depolarizations, and these after depolarizations are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include:

Administration of beta receptor blocking agents which decreases the risk of stress induced arrhythmias. Beta blockers are the first choice in treating Long QT syndrome.

In 2004 it has been shown that genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blockers therapy. Specifically the presence of QTc >500ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients primary prevention with ICD (Implantable Cardioverster Defibrilator) implantaion can be considered.^[2]

Potassium supplementation. If the potassium content in the blood rises, the action potential shortens and due to this reason it is believed that increasing potassium concentration could minimize the occurrence of arrhythmias. It should work best in LQT2 since the HERG channel is especially sensible to potassium concentration, but the use is experimental and not evidence based.
Mexiletine. A sodium channel blocker. In LQT3 the problem is that the sodium channel does not close properly. Mexiletine closes these channels and is believed to be usable when other therapies fail. It should be especially effective in LQT3 but there is no evidence based documentation.
Amputation of the cervical sympathetic chain (left stellectomy). This may be used as an add-on therapy to beta blockers but modern therapy mostly favors ICD implantation if beta blocker therapy fails.

Arrhythmia termination

Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. The only effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillator (ICD). ICD are commonly used in patients with syncopes despite beta blocker therapy, and in patients who have experienced a cardiac arrest.

With better knowledge of the genetics underlying the long QT syndrome, more precise treatments will be readily available.^[3]

Risk stratification

The risk for untreated LQTS patients having events (syncopes or cardiac arrest) can be predicted from their genotype (LQT1-8), gender and corrected QT interval.^[4]

High risk (>50%)

QTc>500 msec LQT1 & LQT2 & LQT3(males)

Intermediate risk (30-50%)

QTc>500 msec LQT3(females)

QTc<500 msec LQT2(females)& LQT3

Low risk (<30%)

QTc<500 msec LQT1 & LQT2 (males)

References

↑ Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug;88(2):782-4. PMID 8339437.
↑ Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004 Sep 15;292(11):1341-4. PMID: 15367556
↑ Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, Keating MT, Mason JW. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996 Sep 1;94(5):1018-22. PMID 8790040
↑ Risk Stratification in the Long-QT Syndrome: N Engl J Med 2003; 349:908-909, Aug 28, 2003. PMID 12944579.

External links

Template:WikiDoc Sources

[1] Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug;88(2):782-4. PMID 8339437.

[2] Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004 Sep 15;292(11):1341-4. PMID: 15367556

[3] Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, Keating MT, Mason JW. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996 Sep 1;94(5):1018-22. PMID 8790040

[4] Risk Stratification in the Long-QT Syndrome: N Engl J Med 2003; 349:908-909, Aug 28, 2003. PMID 12944579.

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 {{CMG}}; '''Associate Editor(s)-In-Chief:''' {{CZ}}
-==Genetics==
-===LQT1===
-LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases.  The LQT1 [[gene]] is {{gene|KCNQ1}} which has been isolated to [[chromosome]] 11p15.5. KCNQ1 codes for the voltage-gated potassium channel [[KvLQT1]] that is highly expressed in the heart.  It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the I<sub>Ks</sub> ion channel, which is responsible for the delayed potassium rectifier current of the [[cardiac action potential]].
-Mutations to the KCNQ1 gene can be inherited in an [[autosomal dominant]] or an [[autosomal recessive]] pattern in the same family.  In the autosomal recessive mutation of this gene, [[homozygous]] mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the I<sub>Ks</sub> ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness.  This variant of LQT1 is known as the [[Jervell and Lange-Nielsen syndrome]].
-Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of [[epinephrine]].  This can also unmark latent carriers of the LQT1 gene.
-Many [[missense mutation]]s of the LQT1 gene have been identified.  These are often associated with a high risk percentage of symptomatic carriers and sudden death.
-===LQT2===
-The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 35 to 45 percent of all cases.  This form of long QT syndrome most likely involves mutations of the ''human ether-a-go-go related gene'' ([[HERG]]) on chromosome 7.  The [[HERG]] gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (I<sub>Kr</sub>). (The I<sub>Kr</sub> current is mainly responsible for the termination of the [[cardiac action potential]], and therefore the length of the QT interval.)  The normally functioning [[HERG]] gene allows protection against early after depolarizations (EADs).
-Most drugs that cause long QT syndrome do so by blocking the I<sub>Kr</sub> current via the [[HERG]] gene.  These include [[erythromycin]], [[terfenadine]], and [[ketoconazole]].  The HERG channel is very sensitive to unintended drug binding due to two [[aromatic]] [[amino acid]]s, the [[tyrosine]] at position 652 and the [[phenylalanine]] at position 656.  These amino acid residues are poised so drug binding to them will block the channel from conducting current.  Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage.
-===LQT3===
-The LQT3 type of long QT syndrome involves mutation of the gene that encodes the alpha subunit of the [[sodium|Na<sup>+</sup>]] ion channel.  This gene is located on chromosome 3p21-24, and is known as [[SCN5A]] (also hH1 and Na<sub>V</sub>1.5).  The mutations involved in LQT3 slow the inactivation of the Na<sup>+</sup> channel, resulting in prolongation of the Na<sup>+</sup> influx during depolarization.  Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.
-A large number of mutations have been characterized as leading to or predisposing LQT3.  Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore mutations in [[SCN5A]] can cause [[Brugada syndrome]], Cardiac Conduction disease and [[dilated cardiomyopathy]]. Rarely some affected individuals can have combinations of these diseases.
-===LQT5===
-is an [[autosomal dominant]] relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to [[Jervell and Lange-Nielsen syndrome]]
-===LQT6===
-is an [[autosomal dominant]] relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1, constituting part of the I<sub>Kr</sub> repolarizing K<sup>+</sup> current.
-===LQT7===
-[[Andersen-Tawil syndrome]] is an [[autosomal dominant]] form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2 which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis and skeletal developmental abnormalities as clinodactyly, low-set ears and [[micrognathia]]. The manifestations are highly variable.<ref>Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). Journal of Clinical Investigation. 2002 Aug;110(3):381-8. PMID 12163457.</ref>
-===LQT8===
-Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly and immune deficiency.
-===LQT9===
-This newly discovered variant is caused by mutations in the membrane structural protein, [[caveolin]]<nowiki>-3</nowiki>.  Caveolins form specific membrane domains called [[caveolae]] in which among others the Na<sub>V</sub>1.5 [[voltage-gated sodium channel]] sits.   Similar to LQT3, these particular mutations increase so-called 'late' sodium current which impairs cellular [[repolarization]].
-===LQT10===
-This novel susceptibility gene for LQT is ''SCN4B'' encoding the protein Na<sub>V</sub>β4, an auxiliary [[subunit]] to the pore-forming Na<sub>V</sub>1.5 (gene:  ''SCN5A'') subunit of the [[voltage-gated sodium channel]] of the heart.  The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current.  Only one mutation in one patient has so far been found.
 ==Associated syndromes==

v t e Electrocardiography
Overview	History of the EKG • EKG interpretation basics • Normal sinus rhythm
EKG Complexes	P wave • QRS complex • ST Segment • T wave • T wave alternans • Tombstone T wave • U wave Osborn wave • H wave • K wave • Delta wave NSSTW changes
EKG Intervals	PR Interval • QRS Interval • ST Interval • QT Interval
Conduction System & Bradycardia	Cardiac pacemaker • SA node • AV node• Bundle of His • Purkinje fibers • Sinus bradycardia • First Degree AV Block • Second Degree AV Block • Complete or Third-Degree AV Block • Concealed conduction • AV Junctional Rhythms • LBBB • LAHB • LPHB • RBBB • Trifascicular block
Atrial Arrhythmias	Sinus tachycardia • Premature Atrial Contractions (PACs) • Ectopic Atrial Rhythm • Paroxysmal Atrial Tachycardia (PAT) • Paroxysmal Atrial Tachycardia (PAT) with Block • Multifocal Atrial Tachycardia (MAT) • Atrial Flutter • Atrial Fibrillation • Wandering atrial pacemaker
Ventricular Arrhythmias	Differential Diagnosis of Tachycardia with a Wide QRS Complex • Accelerated Idioventricular Rhythm • Ventricular Parasystole • Premature Ventricular Contractions (PVCs) • Ventricular tachycardia • Ventricular Fibrillation • Sudden cardiac death
EKG Abnormalities in Disease States	Hypertrophy & Dilatation • Right atrial enlargement • Left atrial enlargement • Biatrial enlargement • Left Ventricular Hypertrophy • Right Ventricular Hypertrophy • Biventricular Hypertrophy • Acute myocardial infarction • NSTEMI • STEMI • Tombstone ST elevation • Right ventricular myocardial infarction • Atrial infarction Pre-excitation Syndromes • Wolff-Parkinson-White Syndrome • Lown Ganong Levine Syndrome • Mahaim Type Preexcitation Cardiomyopathies • Arrhythmogenic Right Ventricular Dysplasia • Dilated Cardiomyopathy • Hypertrophic Cardiomyopathy Drug Effects on the EKG • Adenosine • β-blockers • Digitalis • Quinidine • Procainamide • Disopyramide • Lidocaine • Tocainide and Mexiletine • Phenytoin • Encainide, Flecainide and Propafenone • Amiodarone • Bretylium • Ca Channel Blockers • Phenothiazines • Tricyclic Antidepressants • Lithium Congenital Heart Disease • Dextrocardia • Atrial Septal Defect • Ventricular Septal Defect • Tetralogy of Fallot • Conjoined Twins or Siamese Twins • Congenital heart block Electrolyte Disturbances • Hyperkalemia • Hypokalemia • Hypercalcemia • Hypocalcemia • Nonspecific Changes Other Heart Diseases • Pericarditis • Myocarditis • Tamponade • Heart Transplantation • Sick Sinus Syndrome • Long QT Syndrome Inherited Disease • Brugada Syndrome Systemic Diseases • CNS Disease • Cardiac Tumors Heart Transplantation • EKG Changes in patient with Heart Transplantation Exogenous Effects • Hypothermia • Chest Trauma • Insect Bites • Electric Injuries
Technical Issues and Potential Errors in Interpretation	Artifacts • Lead Placement Errors • The EKG in a Patient with a Pacemaker • EKG in athletes