Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

BC Inherited Arrhythmia Program 211 1033 Davie St Vancouver BC V6E 1M7 Canada

Children's Heart Centre 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Vúvalu 84 15006 Prague Czech Republic

Département de Pédiatrie CHU Ste Justine 3175 chemin Côte Sainte Catherine Montréal QC H3T 1C5 Canada

Department of Arrhythmia and Cardiac Pacing Cardiocentro Pediatrico William Soler 100 y perla Boyeros 10800 Havana Cuba

Department of Cardiology Children's Memorial Health Institute Dzieci Polskich 20 04 730 Warsaw Poland

Department of Electrophysiology German Heart Center Munich Technical University Lazarettstr 3680636 Munich Germany

Department of Pediatric Cardiology Heart Center University of Leipzig Strümpellstrasse 39 Leipzig Germany

Department of Pediatrics A 1 DuPont Hospital For Children 1600 Rockland Rd Wilmington DE 19803 USA

Department of Pediatrics and the Vanderbilt Center for Arrhythmia Research and Therapeutics Vanderbilt University Medical Center and the Monroe Carell Jr Children's Hospital at Vanderbilt 2200 Children's Way Suite 5230 Nashville TN 37232 9119 USA

Department of Pediatrics Children's Hospital Los Angeles 4650 Sunset Blvd 34 Los Angeles CA 90027 USA

Department of Pediatrics Joe DiMaggio Children's Hospital 1150 North 35th Avenue Suite 575 Hollywood FL 33021 USA

Department of Pediatrics University of California at Irvine Medical Center 1140 W La Veta Ave Suite 750 Orange CA 92868 USA

Department of Pediatrics University of Colorado 13123 East 16th Avenue Aurora CO 80045 USA

Department of Pediatrics University of Louisville 601 S Floyd St 602 Louisville KY 40208 USA

Department of Pediatrics University of Michigan 1500 E Medical Center Drive 6303 Ann Arbor MI 48109 USA

Department of Pediatrics University of Rochester 601 Elmwood Ave Box 631 Rochester NY 14642 USA

Department of Pediatrics University of Toronto Hospital for Sick Children 555 University Avenue Toronto Ontario M5G 1X8 Canada

Department of Pediatrics University of Utah 81 N Mario Capecchi Drive Salt Lake City UT 84113 USA

Department of Pediatrics University of Washington 4800 Sand Point Way NE Seattle WA 98105 USA

Department of Pediatrics University of Wisconsin School of Medicine and Public Health 1675 Highland Ave Madison WI 53792 USA

Departments of Pediatrics Medicine Biochemistry and Molecular Biology University of British Columbia 4480 Oak Street Room 1F3 Vancouver BC V6H 3V4 Canada

Division of Cardiology Phoenix Children's Hospital 1919 E Thomas Road 2nd Floor Heart Center Phoenix AZ 85016 USA

Division of Cardiology UNMC CUMC Children's Hospital and Medical Center 8200 Dodge Street Omaha NE 68114 USA

Division of Pediatric Cardiology University of Alabama at Birmingham 1700 6th Ave S Birmingham AL 35233 USA

Nicklaus Children's Hospital 3100 SW 62 Ave Cardiology ACB 2nd Floor Miami FL 33155 USA

Providence Sacred Heart Children's Hospital 101 W 8th Ave Suite 4300E Spokane WA 99204 USA

Royal Children's Hospital MCRI and University of Melbourne 50 Flemington Road Parkville Melbourne 3052 Australia

Stollery Children's Hospital University of Alberta Clinical Sciences Building 8440 112 St NW Edmonton AB T6G 2B7 Canada

000      

00000naa a2200000 a 4500

001      

bmc19001323

003      

CZ-PrNML

005      

20190110101417.0

007      

ta

008      

190107s2018 enk f 000 0|eng||

009      

AR

024    7_

$a 10.1093/europace/euw389 $2 doi

035    __

$a (PubMed)28158428

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a enk

100    1_

$a Roston, Thomas M $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

245    14

$a The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry / $c TM. Roston, Z. Yuchi, PJ. Kannankeril, J. Hathaway, JM. Vinocur, SP. Etheridge, JE. Potts, KR. Maginot, JC. Salerno, MI. Cohen, RM. Hamilton, A. Pflaumer, S. Mohammed, L. Kimlicka, RJ. Kanter, MJ. LaPage, KK. Collins, RA. Gebauer, JD. Temple, AS. Batra, C. Erickson, M. Miszczak-Knecht, P. Kubuš, Y. Bar-Cohen, M. Kantoch, VC. Thomas, G. Hessling, C. Anderson, ML. Young, SHJ. Choi, M. Cabrera Ortega, YR. Lau, CL. Johnsrude, A. Fournier, F. Van Petegem, S. Sanatani,

520    9_

$a Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

650    _2

$a mladiství $7 D000293

650    _2

$a kalsekvestrin $x genetika $7 D002155

650    _2

$a dítě $7 D002648

650    _2

$a mutační analýza DNA $7 D004252

650    _2

$a náhlá srdeční smrt $x epidemiologie $7 D016757

650    _2

$a ženské pohlaví $7 D005260

650    _2

$a genetické markery $7 D005819

650    _2

$a genetická predispozice k nemoci $7 D020022

650    _2

$a dědičnost $7 D040941

650    _2

$a lidé $7 D006801

650    _2

$a mužské pohlaví $7 D008297

650    _2

$a molekulární modely $7 D008958

650    12

$a mutace $7 D009154

650    _2

$a rodokmen $7 D010375

650    _2

$a fenotyp $7 D010641

650    _2

$a prognóza $7 D011379

650    _2

$a konformace proteinů $7 D011487

650    _2

$a registrace $7 D012042

650    _2

$a retrospektivní studie $7 D012189

650    _2

$a rizikové faktory $7 D012307

650    _2

$a ryanodinový receptor vápníkového kanálu $x chemie $x genetika $x metabolismus $7 D019837

650    _2

$a vztahy mezi strukturou a aktivitou $7 D013329

650    _2

$a komorová tachykardie $x diagnóza $x genetika $x mortalita $x patofyziologie $7 D017180

655    _2

$a časopisecké články $7 D016428

655    _2

$a multicentrická studie $7 D016448

655    _2

$a pozorovací studie $7 D064888

700    1_

$a Yuchi, Zhiguang $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Kannankeril, Prince J $u Department of Pediatrics and the Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) Vanderbilt University Medical Center and the Monroe Carell Jr. Children's Hospital at Vanderbilt, 2200 Children's Way, Suite 5230, Nashville, TN 37232-9119, USA.

700    1_

$a Hathaway, Julie $u BC Inherited Arrhythmia Program, 211-1033 Davie St, Vancouver, BC V6E 1M7, Canada.

700    1_

$a Vinocur, Jeffrey M $u Department of Pediatrics, University of Rochester, 601 Elmwood Ave, Box 631, Rochester, NY 14642, USA.

700    1_

$a Etheridge, Susan P $u Department of Pediatrics, University of Utah, 81 N Mario Capecchi Drive Salt Lake City, UT 84113, USA.

700    1_

$a Potts, James E $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Maginot, Kathleen R $u Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, 1675 Highland Ave, Madison, WI 53792, USA.

700    1_

$a Salerno, Jack C $u Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA.

700    1_

$a Cohen, Mitchell I $u Division of Cardiology Phoenix Children's Hospital, 1919 E. Thomas Road, 2nd Floor, Heart Center, Phoenix, AZ 85016, USA.

700    1_

$a Hamilton, Robert M $u Department of Pediatrics, University of Toronto, Hospital for Sick Children, 555 University Avenue Toronto, Ontario M5G 1X8, Canada.

700    1_

$a Pflaumer, Andreas $u Royal Children's Hospital MCRI and University of Melbourne, 50 Flemington Road Parkville, Melbourne 3052, Australia.

700    1_

$a Mohammed, Saira $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Kimlicka, Lynn $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Kanter, Ronald J $u Nicklaus Children's Hospital, 3100 SW 62 Ave, Cardiology ACB - 2nd Floor Miami, FL 33155, USA.

700    1_

$a LaPage, Martin J $u Department of Pediatrics, University of Michigan, 1500 E Medical Center Drive, #6303, Ann Arbor, MI 48109, USA.

700    1_

$a Collins, Kathryn K $u Department of Pediatrics, University of Colorado, 13123 East 16th Avenue, Aurora, CO 80045, USA.

700    1_

$a Gebauer, Roman A $u Department of Pediatric Cardiology, Heart Center, University of Leipzig, Strümpellstrasse 39, Leipzig, Germany.

700    1_

$a Temple, Joel D $u Department of Pediatrics, A. I. DuPont Hospital For Children, 1600 Rockland Rd, Wilmington, DE 19803, USA.

700    1_

$a Batra, Anjan S $u Department of Pediatrics, University of California at Irvine Medical Center, 1140 W. La Veta Ave., Suite 750, Orange, CA 92868, USA.

700    1_

$a Erickson, Christopher $u Division of Cardiology, UNMC/CUMC/Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA.

700    1_

$a Miszczak-Knecht, Maria $u Department of Cardiology, Children's Memorial Health Institute, Dzieci Polskich 20, 04 -730 Warsaw, Poland.

700    1_

$a Kubuš, Peter $u Children's Heart Centre, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Vúvalu 84, 15006, Prague, Czech Republic.

700    1_

$a Bar-Cohen, Yaniv $u Department of Pediatrics, Children's Hospital Los Angeles, 4650 Sunset Blvd #34, Los Angeles, CA 90027, USA.

700    1_

$a Kantoch, Michal $u Stollery Children's Hospital, University of Alberta, Clinical Sciences Building, 8440 112 St NW, Edmonton, AB T6G 2B7, Canada.

700    1_

$a Thomas, Vincent C $u Division of Cardiology, UNMC/CUMC/Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA.

700    1_

$a Hessling, Gabriele $u Department of Electrophysiology, German Heart Center Munich, Technical University, Lazarettstr. 3680636 Munich, Germany.

700    1_

$a Anderson, Chris $u Providence Sacred Heart Children's Hospital, 101 W. 8th Ave. Suite 4300E, Spokane, WA 99204, USA.

700    1_

$a Young, Ming-Lon $u Department of Pediatrics, Joe DiMaggio Children's Hospital, 1150 North 35th Avenue Suite 575, Hollywood, FL 33021, USA.

700    1_

$a Choi, Sally H J $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Cabrera Ortega, Michel $u Department of Arrhythmia and Cardiac Pacing, Cardiocentro Pediatrico William Soler, 100 y perla, Boyeros. 10800, Havana, Cuba.

700    1_

$a Lau, Yung R $u Division of Pediatric Cardiology, University of Alabama at Birmingham, 1700 6th Ave S, Birmingham, AL 35233, USA.

700    1_

$a Johnsrude, Christopher L $u Department of Pediatrics, University of Louisville, 601 S Floyd St #602, Louisville, KY 40208, USA.

700    1_

$a Fournier, Anne $u Département de Pédiatrie, CHU Ste Justine, 3175, chemin Côte Sainte-Catherine, Montréal, QC H3T 1C5 Canada.

700    1_

$a Van Petegem, Filip $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

700    1_

$a Sanatani, Shubhayan $u Departments of Pediatrics/Medicine/Biochemistry & Molecular Biology, University of British Columbia, 4480 Oak Street, Room 1F3, Vancouver, BC, V6H 3V4, Canada.

773    0_

$w MED00149837 $t Europace European pacing, arrhythmias, and cardiac electrophysiology journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology $x 1532-2092 $g Roč. 20, č. 3 (2018), s. 541-547

856    41

$u https://pubmed.ncbi.nlm.nih.gov/28158428 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20190107 $b ABA008

991    __

$a 20190110101620 $b ABA008

999    __

$a ok $b bmc $g 1365207 $s 1039446

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2018 $b 20 $c 3 $d 541-547 $i 1532-2092 $m Europace $n Europace $x MED00149837

LZP    __

$a Pubmed-20190107