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The [[voltage-gated ion channel]] [[mutation]] associated with [[CPVT]] intermittently causes the [[heart]] to develop [[polymorphic ventricular tachycardia]] in response to the natural release of [[catecholamines]]. [[Catecholaminergic polymorphic VT]] may have both [[autosomal dominant]] and [[autosomal recessive]] pattern of [[inheritance]]. The following [[genes]] are associated with [[CPVT]]: | |||
*'''[[ryanodine receptor 2|RyR2]]''': | |||
**[[Mutations]] in [[ryanodine receptor 2|cardiac ryanodine receptor]] gene [[ryanodine receptor 2|RyR2]] accounts for CPVT 1, and majority of the cases (approximately 65%).<ref name="PrioriNapolitano2001">{{cite journal|last1=Priori|first1=Silvia G.|last2=Napolitano|first2=Carlo|last3=Tiso|first3=Natascia|last4=Memmi|first4=Mirella|last5=Vignati|first5=Gabriele|last6=Bloise|first6=Raffaella|last7=Sorrentino|first7=Vincenzo|last8=Danieli|first8=Gian Antonio|title= | |||
Mutations in the Cardiac Ryanodine Receptor Gene ( | |||
hRyR2 | |||
) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia | |||
|journal=Circulation|volume=103|issue=2|year=2001|pages=196–200|issn=0009-7322|doi=10.1161/01.CIR.103.2.196}}</ref><ref name="AckermanPriori2011">{{cite journal|last1=Ackerman|first1=M. J.|last2=Priori|first2=S. G.|last3=Willems|first3=S.|last4=Berul|first4=C.|last5=Brugada|first5=R.|last6=Calkins|first6=H.|last7=Camm|first7=A. J.|last8=Ellinor|first8=P. T.|last9=Gollob|first9=M.|last10=Hamilton|first10=R.|last11=Hershberger|first11=R. E.|last12=Judge|first12=D. P.|last13=Le Marec|first13=H.|last14=McKenna|first14=W. J.|last15=Schulze-Bahr|first15=E.|last16=Semsarian|first16=C.|last17=Towbin|first17=J. A.|last18=Watkins|first18=H.|last19=Wilde|first19=A.|last20=Wolpert|first20=C.|last21=Zipes|first21=D. P.|title=HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)|journal=Europace|volume=13|issue=8|year=2011|pages=1077–1109|issn=1099-5129|doi=10.1093/europace/eur245}}</ref> | |||
**Genetic linkage studies revealed the disease-causing [[locus]] with an [[autosomal dominant]] inheritance pattern on [[chromosome]] [[1q42–q43]].<ref name="SwanPiippo1999">{{cite journal|last1=Swan|first1=Heikki|last2=Piippo|first2=Kirsi|last3=Viitasalo|first3=Matti|last4=Heikkilä|first4=Päivi|last5=Paavonen|first5=Timo|last6=Kainulainen|first6=Katariina|last7=Kere|first7=Juha|last8=Keto|first8=Pekka|last9=Kontula|first9=Kimmo|last10=Toivonen|first10=Lauri|title=Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts|journal=Journal of the American College of Cardiology|volume=34|issue=7|year=1999|pages=2035–2042|issn=07351097|doi=10.1016/S0735-1097(99)00461-1}}</ref> | |||
**[[ryanodine receptor 2|RyR2]] is involved in intracellular [[calcium]] [[homeostasis]] and in the [[excitation-contraction coupling]] of the [[heart]]. | |||
**Mutations in [[ryanodine receptor 2|RYR2]] cause uncontrolled [[calcium]] leakage from the [[sarcoplasmic reticulum]] during electrical [[diastole]], with a subsequent increase in the [[cytosolic]] [[calcium]] concentration.<ref name="JiangXiao2004">{{cite journal|last1=Jiang|first1=D.|last2=Xiao|first2=B.|last3=Yang|first3=D.|last4=Wang|first4=R.|last5=Choi|first5=P.|last6=Zhang|first6=L.|last7=Cheng|first7=H.|last8=Chen|first8=S. R. W.|title=RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)|journal=Proceedings of the National Academy of Sciences|volume=101|issue=35|year=2004|pages=13062–13067|issn=0027-8424|doi=10.1073/pnas.0402388101}}</ref><ref name="PrioriNapolitano2001">{{cite journal|last1=Priori|first1=Silvia G.|last2=Napolitano|first2=Carlo|last3=Tiso|first3=Natascia|last4=Memmi|first4=Mirella|last5=Vignati|first5=Gabriele|last6=Bloise|first6=Raffaella|last7=Sorrentino|first7=Vincenzo|last8=Danieli|first8=Gian Antonio|title= | |||
Mutations in the Cardiac Ryanodine Receptor Gene ( | |||
hRyR2 | |||
) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia | |||
|journal=Circulation|volume=103|issue=2|year=2001|pages=196–200|issn=0009-7322|doi=10.1161/01.CIR.103.2.196}}</ref> | |||
**The increased cytosolic [[calcium]] concentration activates the [[sodium-calcium exchanger]], leading to a transient inward current, and delayed [[after-depolarizations]] that in turn can lead to triggered [[arrhythmias]]. The [[calcium]] leakage is more pronounced in the setting of high [[adrenergic|β-adrenergic]] tone.<ref name="CerroneNoujaim2007">{{cite journal|last1=Cerrone|first1=Marina|last2=Noujaim|first2=Sami F.|last3=Tolkacheva|first3=Elena G.|last4=Talkachou|first4=Arkadzi|last5=O’Connell|first5=Ryan|last6=Berenfeld|first6=Omer|last7=Anumonwo|first7=Justus|last8=Pandit|first8=Sandeep V.|last9=Vikstrom|first9=Karen|last10=Napolitano|first10=Carlo|last11=Priori|first11=Silvia G.|last12=Jalife|first12=José|title=Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia|journal=Circulation Research|volume=101|issue=10|year=2007|pages=1039–1048|issn=0009-7330|doi=10.1161/CIRCRESAHA.107.148064}}</ref><ref name="Knollmann2006">{{cite journal|last1=Knollmann|first1=B. C.|title=Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia|journal=Journal of Clinical Investigation|year=2006|issn=0021-9738|doi=10.1172/JCI29128}}</ref> | |||
Revision as of 09:22, 10 July 2020
The voltage-gated ion channel mutation associated with CPVT intermittently causes the heart to develop polymorphic ventricular tachycardia in response to the natural release of catecholamines. Catecholaminergic polymorphic VT may have both autosomal dominant and autosomal recessive pattern of inheritance. The following genes are associated with CPVT:
- RyR2:
- Mutations in cardiac ryanodine receptor gene RyR2 accounts for CPVT 1, and majority of the cases (approximately 65%).[1][2]
- Genetic linkage studies revealed the disease-causing locus with an autosomal dominant inheritance pattern on chromosome 1q42–q43.[3]
- RyR2 is involved in intracellular calcium homeostasis and in the excitation-contraction coupling of the heart.
- Mutations in RYR2 cause uncontrolled calcium leakage from the sarcoplasmic reticulum during electrical diastole, with a subsequent increase in the cytosolic calcium concentration.[4][1]
- The increased cytosolic calcium concentration activates the sodium-calcium exchanger, leading to a transient inward current, and delayed after-depolarizations that in turn can lead to triggered arrhythmias. The calcium leakage is more pronounced in the setting of high β-adrenergic tone.[5][6]
- ↑ 1.0 1.1 Priori, Silvia G.; Napolitano, Carlo; Tiso, Natascia; Memmi, Mirella; Vignati, Gabriele; Bloise, Raffaella; Sorrentino, Vincenzo; Danieli, Gian Antonio (2001). "Mutations in the Cardiac Ryanodine Receptor Gene (
hRyR2
) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia". Circulation. 103 (2): 196–200. doi:10.1161/01.CIR.103.2.196. ISSN 0009-7322. line feed character in
|title=at position 51 (help) - ↑ Ackerman, M. J.; Priori, S. G.; Willems, S.; Berul, C.; Brugada, R.; Calkins, H.; Camm, A. J.; Ellinor, P. T.; Gollob, M.; Hamilton, R.; Hershberger, R. E.; Judge, D. P.; Le Marec, H.; McKenna, W. J.; Schulze-Bahr, E.; Semsarian, C.; Towbin, J. A.; Watkins, H.; Wilde, A.; Wolpert, C.; Zipes, D. P. (2011). "HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)". Europace. 13 (8): 1077–1109. doi:10.1093/europace/eur245. ISSN 1099-5129.
- ↑ Swan, Heikki; Piippo, Kirsi; Viitasalo, Matti; Heikkilä, Päivi; Paavonen, Timo; Kainulainen, Katariina; Kere, Juha; Keto, Pekka; Kontula, Kimmo; Toivonen, Lauri (1999). "Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts". Journal of the American College of Cardiology. 34 (7): 2035–2042. doi:10.1016/S0735-1097(99)00461-1. ISSN 0735-1097.
- ↑ Jiang, D.; Xiao, B.; Yang, D.; Wang, R.; Choi, P.; Zhang, L.; Cheng, H.; Chen, S. R. W. (2004). "RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)". Proceedings of the National Academy of Sciences. 101 (35): 13062–13067. doi:10.1073/pnas.0402388101. ISSN 0027-8424.
- ↑ Cerrone, Marina; Noujaim, Sami F.; Tolkacheva, Elena G.; Talkachou, Arkadzi; O’Connell, Ryan; Berenfeld, Omer; Anumonwo, Justus; Pandit, Sandeep V.; Vikstrom, Karen; Napolitano, Carlo; Priori, Silvia G.; Jalife, José (2007). "Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia". Circulation Research. 101 (10): 1039–1048. doi:10.1161/CIRCRESAHA.107.148064. ISSN 0009-7330.
- ↑ Knollmann, B. C. (2006). "Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia". Journal of Clinical Investigation. doi:10.1172/JCI29128. ISSN 0021-9738.