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

Background: Serum anti-heart autoantibodies (AHA) and anti-intercalated disk autoantibodies (AIDA) are autoimmune markers in myocarditis. In arrhythmogenic right ventricular cardiomyopathy (ARVC) myocarditis has been reported. To provide evidence for autoimmunity, we searched for AHA and AIDA in ARVC. Methods: We studied: 42 ARVC probands, 23 male, aged 42, interquartile range (IQR) 33;49, 20 from familial and 22 non-familial pedigrees; 37 clinically affected relatives (AR), 24 male aged 35, IQR 18;46; 96 healthy relatives (HR), 49 male, aged 27, IQR 17;45. Serum AHA and AIDA were tested by indirect immunofluorescence on human myocardium and skeletal muscle in 171 of the 175 ARVC individuals and in controls with: non-inflammatory cardiac disease (NICD) (n=160), ischemic heart failure (IHF) (n=141), normal blood donors (NBD) (n=270). Screening of five desmosomal genes was performed in probands; when a sequence variant was identified, cascade family screening followed, blind to immunological results. Results: AHA frequency was higher (36.8%) in probands, AR (37.8%) and HR (25%) than in NICD (1%), IHF (1%) or NBD (2.5%) (p=0.0001). AIDA frequency was higher in probands (8%, p=0.006), in AR (21.6%, p=0.00001) and in HR (14.6% p=0.00001) than in NICD (3.75%), IHF (2%) or NBD (0.3%). AHA positive status was associated with higher frequency of palpitation (p=0.004), ICD implantation (p=0.021), lower left ventricular ejection fraction (LVEF) (p=0.004), AIDA positive status with both lower RV and LVEF (p=0.027 and p=0.027 respectively). AHA and/or AIDA positive status in the proband and/or 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: Presence of AHA and AIDA provides evidence of autoimmunity in the majority of familial and in almost half of sporadic ARVC. In probands and in AR these antibodies were associated with disease severity features; longitudinal studies are needed to clarify whether they may predict ARVC development in HR or if they be a result of manifest ARVC