Long QT Syndrome pathophysiology: Difference between revisions
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==Overview== | ==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== | ==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 [[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. | |||
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 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. | |||
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== | ==References== | ||
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{{WS}} | {{WS}} | ||
[[Category:Cardiology]] | |||
[[Category:Electrophysiology]] | |||
[[Category:Channelopathy]] | |||
[[Category:Genetic disorders]] | |||
[[Category:Syndromes]] | |||
Latest revision as of 15:18, 11 July 2017
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Long QT Syndrome Microchapters |
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Long QT Syndrome pathophysiology On the Web |
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American Roentgen Ray Society Images of Long QT Syndrome pathophysiology |
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Risk calculators and risk factors for Long QT Syndrome pathophysiology |
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.