Long QT Syndrome pathophysiology: Difference between revisions

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Latest revision as of 15:18, 11 July 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Long QT syndrome results from an inherited abnormality in the ion channels of the heart, most commonly potassium channels and sodium channels.^[1]^[2] In long QT syndrome, mutations in the potassium channels lead to a decrease in the potassium efflux during repolarization, whereas gain of function in the sodium channels cause a slow sodium influx during depolarization. The different mutations involved in long QT syndrome culminate in a similar outcome which is the prolongation of both the action potential and the QT interval. Arrhythmia in long QT syndrome involve an abnormal repolarization of the heart.

Pathophysiology

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.

Genetics

Most Long QT syndromes are inherited in an autosomal dominant pattern with variable penetrance,^[3] the exception being Jervell and Lange-Nielsen syndrome (JLNS) which is associated with deafness and is inherited in an autosomal recessive pattern.

Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.

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.

References

↑ Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M; et al. (2003). "Risk stratification in the long-QT syndrome". N Engl J Med. 348 (19): 1866–74. doi:10.1056/NEJMoa022147. PMID 12736279.
↑ Abrams DJ, Macrae CA (2014). "Long QT Syndrome". Circulation. 129 (14): 1524–9. doi:10.1161/CIRCULATIONAHA.113.003985. PMID 24709866.
↑ Priori SG, Napolitano C, Schwartz PJ (1999). "Low penetrance in the long-QT syndrome: clinical impact". Circulation. 99 (4): 529–33. PMID 9927399.

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[pmid12736279-1] Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M; et al. (2003). "Risk stratification in the long-QT syndrome". N Engl J Med. 348 (19): 1866–74. doi:10.1056/NEJMoa022147. PMID 12736279.

[pmid24709866-2] Abrams DJ, Macrae CA (2014). "Long QT Syndrome". Circulation. 129 (14): 1524–9. doi:10.1161/CIRCULATIONAHA.113.003985. PMID 24709866.

[pmid9927399-3] Priori SG, Napolitano C, Schwartz PJ (1999). "Low penetrance in the long-QT syndrome: clinical impact". Circulation. 99 (4): 529–33. PMID 9927399.

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+{|class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;
+|-
+| {{#ev:youtube|https://https://www.youtube.com/watch?v=oFUZeNCox8Q|350}}
+|-
+|}
 __NOTOC__
 {{Long QT Syndrome}}
@@ Line 5: / Line 11: @@
 ==Overview==
+Long QT syndrome results from an inherited abnormality in the ion channels of the heart, most commonly [[potassium channel]]s and [[sodium channel]]s.<ref name="pmid12736279">{{cite journal| author=Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M et al.| title=Risk stratification in the long-QT syndrome. | journal=N Engl J Med | year= 2003 | volume= 348 | issue= 19 | pages= 1866-74 | pmid=12736279 | doi=10.1056/NEJMoa022147 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12736279  }} </ref><ref name="pmid24709866">{{cite journal| author=Abrams DJ, Macrae CA| title=Long QT Syndrome. | journal=Circulation | year= 2014 | volume= 129 | issue= 14 | pages= 1524-9 | pmid=24709866 | doi=10.1161/CIRCULATIONAHA.113.003985 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24709866  }} </ref>  In long QT syndrome, mutations in the [[potassium]] channels lead to a decrease in the [[potassium]] efflux during [[repolarization]], whereas gain of function in the [[sodium channel]]s cause a slow [[sodium]] influx during [[depolarization]].  The different mutations involved in long QT syndrome culminate in a similar outcome which is the prolongation of both the [[action potential]] and the [[QT interval]].  Arrhythmia in long QT syndrome involve an abnormal [[repolarization]] of the heart.
 ==Pathophysiology==
-===Genetics===
+===Mechanism of Arrhythmia Generation===
-The two most common types of LQTS are genetic and drug-induced.  Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the [[ventricular action potential]] (APD), thus lengthening the QT interval.  LQTS can be inherited in an [[autosomal dominant]] or an [[autosomal recessive]] fashion.  The autosomal recessive forms of LQTS tend to have a more severe[[phenotype]], with some variants having associated [[syndactyly]] (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.
+All forms of the long QT syndrome involve an abnormal repolarization of the heart.  The abnormal repolarization causes differences in the "refractoriness" of the [[myocyte]]s.  After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the [[refractory period|refractory periods]], leading to re-entrant ventricular arrhythmias.
-===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]].
+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.
-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.
+The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca<sup>2+</sup> filling of the [[sarcoplasmic reticulum]].  This overload may cause spontaneous Ca<sup>2+</sup> release during repolarization, causing the released Ca<sup>2+</sup> to exit the cell through the 3Na<sup>+</sup>/Ca<sup>2+</sup>-exchanger which results in a net depolarizing current.
+==Genetics==
+Most Long QT syndromes are inherited in an [[autosomal dominant]] pattern with variable penetrance,<ref name="pmid9927399">{{cite journal| author=Priori SG, Napolitano C, Schwartz PJ| title=Low penetrance in the long-QT syndrome: clinical impact. | journal=Circulation | year= 1999 | volume= 99 | issue= 4 | pages= 529-33 | pmid=9927399 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9927399  }} </ref> the exception being Jervell and Lange-Nielsen syndrome (JLNS) which is associated with deafness and is inherited in an autosomal recessive pattern.
-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.
+Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the [[ventricular action potential]] (APD), thus lengthening the QT interval.  LQTS can be inherited in an [[autosomal dominant]] or an [[autosomal recessive]] fashion.  The autosomal recessive forms of LQTS tend to have a more severe [[phenotype]], with some variants having associated [[syndactyly]] (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.
-===LQT2===
+===Associated Syndromes===
-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==
 A number of syndromes are associated with LQTS.
-===Jervell and Lange-Nielsen syndrome===
+===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
@@ Line 64: / Line 36: @@
 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===
-[[Romano-Ward syndrome]] is an autosomal dominant form of LQTS that is ''not''associated with deafness.
+[[Romano-Ward syndrome]] is an [[autosomal dominant]] form of LQTS that is ''not'' associated with [[deafness]].
 ==References==
@@ Line 75: / Line 47: @@
 {{WS}}
+[[Category:Cardiology]]
+[[Category:Electrophysiology]]
+[[Category:Channelopathy]]
+[[Category:Genetic disorders]]
+[[Category:Syndromes]]