Dilated cardiomyopathy (DCM), the third most common cause of heart failure and the leading cause for heart transplantation (HTX), may be familial/genetic, viral and/or immune-mediated. Experimental and clinical data indicate that in a sizable proportion of patients myocarditis and DCM represent the acute and chronic forms of an organ-specific heart autoimmune disease, occurring in genetically predisposed subjects, with or without a recognized viral trigger. Autoimmune features in human myocarditis/DCM include: a) familial aggregation, b) a weak association with HLA-DR4, c) lymph mononuclear cell infiltrates, abnormal expression of HLA class II and adhesion molecules on endomyocardial biopsy (EMB) in the absence of viral genome by molecular techniques in index patients and family members, d) experimental models of both antibody-mediated and cell-mediated autoimmune myocarditis/DCM following immunization with relevant autoantigen(s) under control of both major histocompatibility complex (MHC) and non-MHC genes, some of which are in common with those associated with genetic control of Type 1 diabetes and other autoimmune diseases, and e) increased levels of circulating cytokines and anti-heart autoantibodies (AHA), directed against multiple antigens, in patients and family members and in about 60% of familial and nonfamilial pedigrees. AHA in myocarditis/DCM may be directed against mitochondrial proteins, cardiac myosin heavy chain, cardiac b1-adrenergic receptors, muscarinergic receptors, the sarcolemmal Na-K-ATPase, cardiac troponin I (cTNI), and other yet unknown targets. AHA predict DCM development among relatives, years before disease onset. Some AHA, e.g antibodies against the ADP/ATP carrier, cardiac myosin, cardiac b1-adrenergic receptors, and cTNI have been shown to possess functional effects on cardiac myocytes in vitro, in animals and possibly in a DCM subset, responsive to extracorporeal immunoadsorption (IA). This is the rationale for the clinical application of IA in an ongoing randomized sham-controlled, double-blind multicenter trial in end-stage DCM. In addition, some AHA, being associated with phases of activation/relapse of the autoimmune process, may provide negative prognostic markers.
The aim of the study by Doesch et al. was to investigate the prognostic value of cTNI-autoantibodies by enzyme-linked immunosorbent assay (ELISA), including 249 patients with DCM and 141 patients with ischemic cardiomyopathy (ICM). cTNI-autoantibodies (titer of ≥ 1:40) were detected in 18.7% of patients. In TNI-autoantibody positive patients mean left ventricular ejection fraction (LVEF) was 27.6 ± 5.8%, compared to 25.8 ± 5.9% in TNI-autoantibody negative patients, P = 0.03. The combined end-point of death (n = 118, 30.3% of total) or HTX (n = 44, 11.3% of total) was reached in 162 patients (41.5% of total). Kaplan–Meier analysis demonstrated superior survival (combined end-point of death or HTX in patients with DCM versus ICM (P = 0.0198) and TNI- autoantibody positive patients versus TNI-autoantibody negative patients (P = 0.0348). Further subgroup analysis revealed a favorable outcome in TNI-positive patients with DCM (P = 0.0334), whereas TNI-autoantibody status in patients with ICM was not associated with survival. In subsequent multivariate Weibull-analysis, a positive TNI serostatus was associated with a lower all-cause mortality in DCM patients (P = 0.0492), but not ICM. The authors conclude that this might indicate a prophylactic effect of TNI-autoantibodies in DCM.
The study by Doesch et al. apparently contrasts with most data published until now, showing detrimental effects of cTNI autoantibodies. There are explanations for this apparent discrepancy. Firstly, the number of autoantibody-positive patients (42 with DCM and 31 with ICM) was rather small for subgroup analysis of outcome. Association of negative autoantibody status with all-cause mortality was of borderline significance in multivariate analysis (p = 0.049). Secondly, at baseline the ICM group was older, had lower LVEF, lower VO2 max, a higher proportion of patients in NYHA class III-IV. Thus, it is likely to represent a more advanced heart failure cohort. In a prospective study by Caforio et al. AHA titers were reduced in end-stage DCM. Thus, DCM and ICM should be matched in terms of heart failure stage to detect potential differences in outcome related to autoantibody status. Thirdly, at least two epitopes of cTnI can induce myocardial damage in murine models. The exact binding site of the cTNI antibodies measured in the present study remains unclear, thus it may be that the cTNI detected by ELISA are not those that have been proven to be detrimental for cardiac myocytes in previous studies. Epitope mapping data on ELISA positive sera would be of interest.
Basic Res Cardiol. 2011 Jan;106(1):25-35. Epub 2010 Oct 20.
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