Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations

被引：113

作者：

Dominguez, Fernando ^{[1
,2
,3
,4
]}

Cuenca, Sofia ^{[3
,5
]}

Bilinska, Zofia ^{[6
,33
]}

Toro, Rocio ^{[7
]}

Villard, Eric ^{[4
,8
]}

Barriales-Villa, Roberto ^{[3
,9
,10
]}

Pablo Ochoa, Juan ^{[11
,12
]}

Asselbergs, Folkert ^{[13
,14
,15
,16
]}

Sammani, Arjan ^{[13
]}

Franaszczyk, Maria ^{[17
]}

Akhtar, Mohammed ^{[4
,18
]}

Jose Coronado-Albi, Maria ^{[19
]}

Rangel-Sousa, Diego ^{[20
]}

Rodriguez-Palomares, Jose F. ^{[3
,21
]}

Jimenez-Jaimez, Juan ^{[22
]}

Manuel Garcia-Pinilla, Jose ^{[3
,23
]}

Ripoll-Vera, Tomas ^{[24
]}

Victoria Mogollon-Jimenez, Maria ^{[25
]}

Fontalba-Romero, Ana ^{[26
]}

Garcia-Medina, Dolores ^{[27
]}

Palomino-Doza, Julian ^{[3
,28
]}

de Gonzalo-Calvo, David ^{[3
,29
,30
]}

Cicerchia, Marcos ^{[11
]}

Salazar-Mendiguchia, Joel ^{[11
]}

Salas, Clara ^{[3
,31
]}

Pankuweit, Sabine ^{[32
]}

Hey, Thomas Morris

Mogensen, Jens

Barton, Paul J. ^{[34
,35
]}

Charron, Philippe ^{[4
,8
]}

Elliott, Perry ^{[4
,18
]}

Garcia-Pavia, Pablo ^{[1
,3
,4
,36
]}

机构：

[1] Hosp Univ Puerta de Hierro, Dept Cardiol, Heart Failure & Inherited Cardiac Dis Unit, Manuel de Falla 2, Madrid 28222, Spain

[2] CNIC, Myocardial Biol Program, Madrid, Spain

[3] Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain

[4] European Reference Network Rare & Low Prevalence, Madrid, Spain

[5] Hosp Gen Univ Gregorio Maranon, Dept Cardiol, Inherited Cardiac Dis Unit, Madrid, Spain

[6] Cardinal Stefan Wyszynski Inst Cardiol, Unit Screening Studies Inherited Cardiovasc Dis, Warsaw, Poland

[7] Inst Res & Innovat Biomed Sci Cadiz INiBICA, Sch Med, Med Dept, Cadiz, Spain

[8] Hop La Pitie Salpetriere, AP HP, Referral Ctr Inherited Cardiac Dis, ICAN,INSERM,UMRS1166, Paris, France

[9] Inst Invest Biomed A Coruna INIBIC, La Coruna, Spain

[10] Univ A Coruna, Complexo Hosp Univ A Coruna, Serv Galego Saude SERGAS, Inherited Cardiovasc Dis Unit,Cardiol Serv, La Coruna, Spain

[11] Hlth Code, Cardiol Dept, La Coruna, Spain

[12] Univ A Coruna, Grp Invest Cardiovasc GRINCAR, La Coruna, Spain

[13] Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands

[14] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England

[15] UCL, Farr Inst Hlth Informat Res, London, England

[16] UCL, Inst Hlth Informat, London, England

[17] Cardinal Stefan Wyszynski Inst Cardiol, Dept Med Biol, Mol Biol Lab, Warsaw, Poland

[18] St Bartholomews Hosp, London, England

[19] Hosp Univ Puerta de Hierro, Confocal Microscopy Unit, Madrid, Spain

[20] Virgen del Rocio Univ Hosp, Dept Cardiol, Heart Failure & Heart Transplantat Unit, Seville, Spain

[21] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Inst Recerca VHIR, Dept Cardiol, Barcelona, Spain

[22] Hosp Univ Virgen de las Nieves, Cardiol Dept, Granada, Spain

[23] Hosp Univ Virgen de la Victoria, Dept Cardiol, Heart Failure & Familial Cardiomyopathies Unit, IBIMA, Malaga, Spain

[24] Hosp Univ Son Llatzer, Cardiol Dept, Mallorca, Spain

[25] Hosp San Pedro de Alcantara, Cardiol Dept, Caceres, Spain

[26] Hosp Univ Marques de Valdecilla, Santander, Spain

[27] Hosp Univ Virgen de Valme, Cardiol Dept, Seville, Spain

[28] Hosp Univ 12 Octubre, Hereditary Cardiopathies Unit, Madrid, Spain

[29] CSIC, Inst Biomed Res Barcelona IIBB, Barcelona, Spain

[30] Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain

[31] Hosp Univ Puerta de Hierro, Dept Pathol, Madrid, Spain

[32] Philipps Univ Marburg, Univ Hosp Giessen & Marburg, Dept Cardiol, Marburg, Germany

[33] Univ Southern Denmark, Odense Univ Hosp, Cardiol Dept, Odense, Denmark

[34] Imperial Coll London, Natl Heart & Lung Inst, London, England

[35] Royal Brompton & Harefield NHS Fdn Trust London, Cardiovasc Res Ctr, London, England

[36] UFV, Madrid, Spain

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2018年 / 72卷 / 20期

基金：

英国医学研究理事会;

关键词：

BAG3; dilated cardiomyopathy; genetics; prognosis; GENETIC ISSUES; HEART-FAILURE; ASSOCIATION; AUTOPHAGY; VARIANTS;

D O I：

10.1016/j.jacc.2018.08.2181

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood. OBJECTIVES This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. METHODS The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 +/- 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. RESULTS At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 +/- 13.2 years vs. 40.7 +/- 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Mate sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. CONCLUSIONS DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations. (C) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

引用

页码：2471 / 2481

页数：11

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