Evidence From Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy Associations of Circulating Anti-Heart and Anti-Intercalated Disk Autoantibodies With Disease Severity and Family History

被引:77
作者
Caforio, Alida L. P. [1 ]
Re, Federica [6 ]
Avella, Andrea [6 ]
Marcolongo, Renzo [2 ]
Baratta, Pasquale [6 ]
Seguso, Mara [3 ]
Gallo, Nicoletta [3 ]
Plebani, Mario [3 ]
Izquierdo-Bajo, Alvaro [1 ]
Cheng, Chun-Yan [1 ]
Syrris, Petros [7 ,8 ]
Elliott, Perry M. [7 ,8 ]
d'Amati, Giulia [9 ]
Thiene, Gaetano [4 ]
Basso, Cristina [4 ]
Gregori, Dario [5 ]
Iliceto, Sabino [1 ]
Zachara, Elisabetta [6 ]
机构
[1] Univ Padua, Dept Cardiac Thorac Vasc Sci & Publ Hlth, Div Cardiol, Via N Giustiniani 2, I-35100 Padua, Italy
[2] Univ Padua, Dept Med Hemat & Clin Immunol, Padua, Italy
[3] Univ Padua, Dept Lab Med, Padua, Italy
[4] Univ Padua, Cardiovasc Pathol Unit, Padua, Italy
[5] Univ Padua, Dept Cardiac Thorac Vasc Sci & Publ Hlth, Stat, Padua, Italy
[6] San Camillo Hosp, Cardiol Div 1, Rome, Italy
[7] UCL, London, England
[8] St Bartholomews Hosp, Barts Heart Ctr, Inherited Cardiac Dis Unit, London, England
[9] Sapienza Univ Rome, Dept Radiol Oncol & Anatomopathol Sci, Rome, Italy
关键词
arrhythmogenic right ventricular dysplasia; autoimmunity; autoantibodies; CARDIAC AUTOANTIBODIES; GENETIC-VARIANTS; MUTATIONS; DIAGNOSIS; MYOCARDITIS; GUIDELINES; DYSPLASIA; PHENOTYPE; DYSTROPHY; STANDARDS;
D O I
10.1161/CIRCULATIONAHA.119.043931
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Serum anti-heart autoantibodies (AHAs) and anti-intercalated disk autoantibodies (AIDAs) are autoimmune markers in myocarditis. Myocarditis has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC). To provide evidence for autoimmunity, we searched for AHAs and AIDAs in ARVC. Methods: We studied: 42 ARVC probands, 23 male, aged 42, interquartile range 33-49, 20 from familial and 22 nonfamilial pedigrees; 37 clinically affected relatives (ARs), 24 male aged 35, interquartile range 18-46; and 96 healthy relatives, 49 male, aged 27, interquartile range 17-45. Serum AHAs and AIDAs were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with noninflammatory cardiac disease (n=160), ischemic heart failure (n=141), and healthy blood donors (n=270). Screening of 5 desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunologic results. Results: AHA frequency was higher (36.8%) in probands, ARs (37.8%), and healthy relatives (25%) than in noninflammatory cardiac disease (1%), ischemic heart failure (1%), or healthy blood donors (2.5%; P=0.0001). AIDA frequency was higher in probands (8%, P=0.006), in ARs (21.6%, P=0.00001), and in healthy relatives (14.6%, P=0.00001) than in noninflammatory cardiac disease (3.75%), ischemic heart failure (2%), or healthy blood donors (0.3%). AHA-positive status was associated with higher frequency of palpitation (P=0.004), implantable cardioverter defibrillator implantation (P=0.021), lower left ventricular ejection fraction (P=0.004), AIDA-positive status with both lower right ventricular and left ventricular ejection fractions (P=0.027 and P=0.027, respectively). AHA- and/or AIDA-positive status in the proband and at least one of the respective relatives was more common in familial (17/20, 85%) than in sporadic (10/22, 45%) pedigrees (P=0.007). Conclusions: The presence of AHAs and AIDAs provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in ARs, these antibodies were associated with features of disease severity. Longitudinal studies are needed to clarify whether they may predict ARVC development in healthy relatives or if they be a result of manifest ARVC.
引用
收藏
页码:1238 / 1248
页数:11
相关论文
共 35 条
[1]  
[Anonymous], 2018, R LANG ENV STAT COMP
[2]  
[Anonymous], 2002, Likelihood, Bayesian, and MCMC methods in quantitative genetics Internet, DOI DOI 10.1007/B98952
[3]   Arrhythmogenic right ventricular cardiomyopathy - Dysplasia, dystrophy, or myocarditis? [J].
Basso, C ;
Thiene, G ;
Corrado, D ;
Angelini, A ;
Nava, A ;
Valente, M .
CIRCULATION, 1996, 94 (05) :983-991
[4]   Arrhythmogenic right ventricular cardiomyopathy [J].
Basso, Cristina ;
Corrado, Domenico ;
Marcus, Frank I. ;
Nava, Andrea ;
Thiene, Gaetano .
LANCET, 2009, 373 (9671) :1289-1300
[5]   CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].
BENJAMINI, Y ;
HOCHBERG, Y .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300
[6]   Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis [J].
Caforio, A. L. P. ;
Brucato, A. ;
Doria, A. ;
Brambilla, G. ;
Angelini, A. ;
Ghirardello, A. ;
Bottaro, S. ;
Tona, F. ;
Betterle, C. ;
Daliento, L. ;
Thiene, G. ;
Iliceto, S. .
HEART, 2010, 96 (10) :779-784
[7]   Prospective familial assessment in dilated cardiomyopathy - Cardiac autoantibodies predict disease development in asymptomatic relatives [J].
Caforio, Alida L. P. ;
Mahon, Niall G. ;
Baig, Kamran ;
Tona, Francesco ;
Murphy, Ross T. ;
Elliott, Perry M. ;
McKenna, William J. .
CIRCULATION, 2007, 115 (01) :76-83
[8]   Passive transfer of affinity-purified anti-heart autoantibodies (AHA) from sera of patients with myocarditis induces experimental myocarditis in mice [J].
Caforio, Alida L. P. ;
Angelini, Annalisa ;
Blank, Miri ;
Shani, Alice ;
Kivity, Shaye ;
Goddard, Gisele ;
Doria, Andrea ;
Schiavo, Alessandro ;
Testolina, Martina ;
Bottaro, Stefania ;
Marcolongo, Renzo ;
Thiene, Gaetano ;
Iliceto, Sabino ;
Shoenfeld, Yehuda .
INTERNATIONAL JOURNAL OF CARDIOLOGY, 2015, 179 :166-177
[9]   Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases [J].
Caforio, Alida L. P. ;
Pankuweit, Sabine ;
Arbustini, Eloisa ;
Basso, Cristina ;
Gimeno-Blanes, Juan ;
Felix, Stephan B. ;
Fu, Michael ;
Helio, Tiina ;
Heymans, Stephane ;
Jahns, Roland ;
Klingel, Karin ;
Linhart, Ales ;
Maisch, Bernhard ;
McKenna, William ;
Mogensen, Jens ;
Pinto, Yigal M. ;
Ristic, Arsen ;
Schultheiss, Heinz-Peter ;
Seggewiss, Hubert ;
Tavazzi, Luigi ;
Thiene, Gaetano ;
Yilmaz, Ali ;
Charron, Philippe ;
Elliott, Perry M. .
EUROPEAN HEART JOURNAL, 2013, 34 (33) :2636-+
[10]   EVIDENCE FROM FAMILY STUDIES FOR AUTOIMMUNITY IN DILATED CARDIOMYOPATHY [J].
CAFORIO, ALP ;
KEELING, PJ ;
ZACHARA, E ;
MESTRONI, L ;
CAMERINI, F ;
MANN, JM ;
BOTTAZZO, GF ;
MCKENNA, WJ .
LANCET, 1994, 344 (8925) :773-777