Published online before print December 18, 2006, doi: 10.1161/CIRCULATIONAHA.106.641472
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(Circulation. 2007;115:76-83.)
© 2007 American Heart Association, Inc.
Heart Failure |
Prospective Familial Assessment in Dilated Cardiomyopathy
Cardiac Autoantibodies Predict Disease Development in Asymptomatic Relatives
From The Heart Hospital (A.L.P.C., N.G.M., M.K.B., R.T.M., P.M.E., W.J.M.), University College, London, United Kingdom. Drs Caforio and Tona are currently with the Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences, University of Padua, Padua, Italy; Dr Mahon is currently with Mater Misericordiae University Hospital, Dublin, Ireland; Dr Baig is currently with Nottingham City Hospital, Nottingham, United Kingdom; and Dr Murphy is currently with St James Hospital, Dublin, Ireland.
Correspondence to Alida L.P. Caforio, MD, PhD, Division of Cardiology, Department of Cardiological, Thoracic and Vascular Sciences, University of Padova-Policlinico, Centro V. Gallucci, Via Giustiniani, 2, 35128 Padova, Italy. E-mail alida.caforio{at}unipd.it
Received May 22, 2006; accepted November 1, 2006.
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Background— In autoimmune disorders, circulating autoantibodies identify healthy relatives at risk years before clinical presentation. Healthy relatives of patients with dilated cardiomyopathy (DCM) who have echocardiographic changes, including left ventricular enlargement or depressed fractional shortening at baseline, have increased medium-term risk for DCM development. Approximately one third of relatives have serum anti-heart autoantibodies (AHAs) at baseline; we intended to assess their potential role in predicting DCM development.
Methods and Results— Baseline evaluation, including electrocardiography, echocardiography, and AHA, was performed in 592 asymptomatic relatives of 169 consecutive DCM patients (291 males and 301 females; mean age 36±16 years). Relatives were classified in accordance with published echocardiographic criteria; those who did not have DCM were followed up (median of 58 months). DCM among relatives was diagnosed by echocardiography at follow-up. Of the 592 individuals evaluated, 77% were assessed as normal, 4.4% as having DCM, and 19% as possibly affected on the basis of depressed fractional shortening without ventricular dilatation in 17 and left ventricular enlargement without systolic dysfunction in 94. Five-year follow-up of 311 relatives revealed that 26 had progressed (13 to DCM, 11 to left ventricular enlargement, and 2 to depressed fractional shortening). Relatives who developed DCM were more frequently AHA-positive than those who did not (69% versus 37%, P=0.02). Five-year probability of progression to DCM, among normal or possibly affected relatives, was higher in AHA-positive cases (P=0.03). By Cox regression, positive AHAs at baseline were independent predictors of progression (RR 2.26, CI 1 to 5.1, P=0.03).
Conclusions— Among healthy relatives of DCM patients, AHAs are independent predictors of disease development within 5 years.
Key Words: cardiomyopathy • antibodies • immunology • inflammation
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Introduction |
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In autoimmune disorders, circulating organ-specific autoantibodies are detected in asymptomatic relatives of affected index patients years before disease presentation1–3 and are useful serological markers for subjects at risk.1–4 Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with multifactorial pathogenesis.5,6 It may be familial/genetic, viral, and/or immune.5–7 Autoimmunity is recognized to play a pivotal role in the pathogenesis of a substantial proportion of cases, possibly triggered by various causes of cardiac injury in genetically predisposed individuals.7,8–10 Circulating autoantibodies to distinct cardiac autoantigens, including
- and ß-myosin heavy chain, are found in animal models11,12 and in humans,13–22 which represent autoimmune markers in a subset of patients.1,7–9,13 With indirect immunofluorescence, organ- and disease-specific anti-heart autoantibodies (AHAs) are found in 
30% of DCM patients at clinical presentation22 and in 20% to 30% of their symptom-free relatives.7 We have reported that symptom-free relatives of DCM patients with subtle echocardiographic changes, in particular, left ventricular enlargement (LVE) or depressed fractional shortening (dFS) at baseline, have increased medium-term risk for DCM development.23 Healthy relatives with or without LVE or dFS have serum AHAs at baseline.7 These relatives have other features of immune activation, including cytokine activation in peripheral blood and intramyocardial inflammation,24,25 and reduced peak oxygen consumption.26
Clinical Perspective p 83
We hypothesized that similar to other autoimmune disorders,1–4 AHAs, found in asymptomatic relatives at initial family evaluation,7 might identify at a preclinical stage those at risk of DCM. In the present study, we assessed the potential role of AHAs, obtained as part of the baseline clinical and immunologic characterization of healthy relatives, in predicting DCM development.
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Methods |
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Probands and Relatives
Study subjects were 592 asymptomatic first- or second-degree relatives (291 males; age 36±16 years; 248 from 54 familial pedigrees and 344 from the 115 nonfamilial pedigrees) of 169 consecutive DCM probands (127 males; age 43±13 years). The study protocol was approved by the human research committee at St George’s Hospital, London, United Kingdom; informed consent was obtained from patients and their relatives.23 Sera for AHA testing were taken at control evaluation as part of the routine immunologic assessment for possible DCM. The diagnosis of DCM was based on World Health Organization criteria.5 Probands were evaluated by noninvasive clinical and invasive examination, including coronary angiography and endomyocardial biopsy where indicated.27 We classified DCM as familial if at least 1 relative (in addition to the proband) had DCM during life or at postmortem examination or if there was a history of unexplained sudden cardiac death before the age of 30 years.7,23
Family screening was offered irrespective of the presence or absence of an overt family history, and inclusion was based on willingness to participate. Assessment of asymptomatic relatives included medical history, clinical examination, 12-lead ECG, 2D echocardiogram, and AHA testing.23 Relatives assessed as having DCM proceeded to the same full evaluation as for probands.23
Echocardiographic Criteria
2D echocardiograms were performed by trained operators working in a dedicated DCM clinic who were unaware of the clinical data. Measurements of chamber dimensions and wall thickness were obtained at the mitral valve–tip level from 2D-guided M-mode or short-axis-view recordings. Predicted normal values for the left ventricular end-diastolic cavity dimension (LVDD) were calculated from Henry’s formula and corrected for age and body surface area (BSA),28 as follows: predicted LVDD=45.3 BSA1/3–0.03(age)–7.2±12%.28 The percent predicted LVDD (%LVDD) was calculated as (measured LVDD/predicted LVDD)x100. LVE was defined as %LVDD 
112 of predicted normal values; dFS was defined as percent fractional shortening (%FS) 
25.28 Using these cutoff levels, asymptomatic relatives were classified as either normal (%LVDD <112 and FS >25); possibly affected, with either LVE (%LVDD 112 and %FS >25) or dFS (%LVDD <112, %FS 25); or as having DCM (%LVDD 112 and %FS 25).7,23,26
Follow-Up of Asymptomatic Relatives
We offered follow-up evaluation, including clinical examination, 12-lead ECG, and 2D echocardiogram, to all relatives regardless of outcome of initial assessment, and we based inclusion on their willingness to participate and their geographic availability. Relatives initially classified as having LVE or dFS were offered annual follow-up, and those found to be normal with positive AHAs had 2-year follow-up. No treatment during follow-up was initiated unless criteria for DCM were fulfilled. AHA-negative individuals who were assessed as normal were reevaluated at a median of 4 years. As part of a larger follow-up program,23 132 AHA-negative normal individuals were studied. Clinical and echocardiographic follow-up was available in 311 relatives initially classified as normal or as having LVE or dFS.
AHA Testing by Standard Indirect Immunofluorescence
For AHA detection, sera were tested by standard indirect immunofluorescence.7,22 The frequency of AHAs in healthy relatives of DCM patients was compared with that observed in our established control groups of noninflammatory heart disease (n=160, 80 males, age 37±17 years, of whom 55 had rheumatic heart disease, 67 had hypertrophic cardiomyopathy, and 38 had congenital defects), ischemic heart disease (n=141, 131 males, age 44±14 years), and normal subjects (n=270, 123 males, age 35±11).7,13,22 Forty-one of the 141 ischemic patients (age 47±12 years, 28 males; 31 in New York Heart Association class III and 10 in class IV) had suffered a documented myocardial infarction 6 months to 10 years (median 2 years) previously; ejection fraction ranged from 16% to 44% (mean 30±7%).7
Statistical Analysis
Results for quantitative features are given as mean±SD. Student t test, 1-way ANOVA, 
2, or Fisher exact test was used as appropriate. The Kaplan-Meier method was used to construct life tables of the probability of survival free from progression to DCM or from any progression (from normal, LVE, or dFS to DCM and from normal to LVE or dFS). The equality of the survival distributions was tested by log-rank test. Multivariable analysis of potential risk factors for progression was performed by the stepwise proportional hazard method of Cox. Results are expressed with the relative risk (RR) ratios and their associated 95% CIs. Variables identified as significant by univariate analysis were included in multivariable analysis. All probability values were 2-tailed; probability values below 0.05 were considered to indicate statistical significance. All statistical analyses were performed with the SPSS statistical software package for Windows, version 13.0 (SPSS Inc, Chicago, Ill).
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Baseline Features and AHA Status of Relatives at Initial Evaluation
At baseline evaluation of the 592 asymptomatic relatives, 455 (77%) were assessed as normal, 26 (4.4%) as having DCM, and 111 (19%) as possibly affected, of whom 17 (3%) had dFS and 94 (16%) had LVE. AHAs of IgG class were detected in 188 relatives (32%); the frequency of AHAs was higher (P<0.0001) in healthy relatives (32%) than in controls with noninflammatory heart disease (1%) or ischemic heart disease (1%) or normal blood donors (2.5%). AHAs were more common in those relatives classified as having asymptomatic DCM (13/26, 50%) than in the other relatives (175/566, 31%; P=0.04). AHA titers were as follows: 1/10 in 113 positive sera (60%), 1/20 in 54 (28%), and 1/40 or higher in 21 (11%). The proportion of first-degree relatives was higher in nonfamilial pedigrees; relatives from familial DCM cases had higher LVDD, higher LVDD%, and lower %FS (Table 1). High-titer AHAs (1/20 or higher) were more frequent in familial pedigrees (P=0.0001; Table 1). In 112 (66%) of the pedigrees, AHAs were found in the proband and/or in at least 1 family member and were more common among relatives with AHA-positive probands (41%) than among those with negative probands (34%, P=0.001; Table 2). AHAs were also more common in familial than in nonfamilial cases (98/248, 39.5% versus 90/344, 26%; P=0.0001). When features were compared after exclusion of the 26 relatives assessed as having asymptomatic DCM at baseline, relatives from familial DCM cases still had lower %FS and higher %LVDD (34±6 versus 36±6, P=0.001, and 106±9 versus 104±9, P=0.03, respectively) and a higher frequency of AHA (85/222 versus 90/344, P=0.002), but the proportions of relatives with LVE or dFS were similar.
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Baseline features did not differ in asymptomatic relatives with and without AHA, except for a higher proportion of pedigrees with positive AHAs in familial than in nonfamilial DCM (45/54, 83% versus 67/115, 58%; P=0.001). Similar proportions of relatives with and without AHAs were classified as possibly affected (LVE or dFS). This also applied when features were compared after exclusion of the 26 asymptomatic relatives who were found to have DCM at baseline.
Univariate and Multivariable Risk Factor Analysis for Disease Development According to Antibody Status
When baseline features were compared in relatives with (n=311) or without (n=255) follow-up, those who were followed up were younger (32±14 versus 40±18 years, P=0.0001), were more frequently AHA-positive (40% versus 22%, P=0.0001), were from familial pedigrees 44% versus 33% of the time (P=0.009), and had a higher prevalence of LVE or dFS (30% versus 6%, P=0.0001), but a substantial number (42%) were assessed as normal and AHA-negative.
Median follow-up time was 58 months (range 1 to 132 months) in all relatives and 54 months (range 1 to 109 months) when those relatives with DCM at family screening were excluded, and follow-up time was shorter in those with LVE or dFS (with or without positive AHAs) than in normal and AHA-negative relatives (54±26 versus 64±26 months, P=0.001). At follow-up, 26 (8%) of the 311 normal or possibly affected asymptomatic relatives progressed (13 to DCM, 11 to LVE, and 2 to dFS). Table 3 shows baseline features of relatives with or without progression to DCM. Relatives who developed DCM had higher mean LVDD, had lower %FS, had higher %LVDD, were more frequently AHA-positive, and were more commonly classified as having LVE or dFS than those who did not develop DCM. The same applied to progression to DCM, LVE, or dFS (Table 4). Positive AHAs were weakly but not significantly associated with progression among relatives of AHA-negative probands; 15% of AHA-positive relatives progressed versus 6% of AHA-negative relatives (P=0.08; Table 5). Similar results were obtained when relatives from familial and nonfamilial DCM probands were analyzed separately.
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By Kaplan-Meier analysis, 5-year probability of survival free from progression to DCM (Figure 1), as well as to DCM, LVE, or dFS (Figure 2), among relatives initially classified as normal or as having LVE or dFS was lower in AHA-positive cases (P=0.03 and P=0.02, respectively). Probability of survival free from progression to DCM, LVE, or dFS among relatives initially classified as normal was also lower in those with positive AHAs (P=0.04; Figure 3). Cox regression, with the inclusion of those variables identified as significant at univariate analysis, demonstrated positive AHAs at baseline as being an independent predictor of progression to DCM, LVE, or dFS during follow-up (P=0.03, RR=2.26, 95% CI 1 to 5.1; Table 6). When only relatives of AHA-negative probands were included in the analysis, AHA-positive status did not attain statistical significance (P=0.3, RR=1.97, 95% CI 0.75 to 3.19; Table 6). The sensitivities and specificities of AHAs alone or in conjunction with an abnormal echocardiogram as predictors of progression are shown in Table 7.
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AHAs as Immune Markers of Disease Risk in DCM
In the present study, organ-specific AHAs, detected in 32% of asymptomatic relatives of both familial and nonfamilial DCM probands, were independent predictors of progression to DCM, LVE, or dFS at 5-year follow-up. In autoimmune disease, circulating autoantibodies are useful markers for identifying subjects at risk,1–4 including those who are genetically related to the index patients, such as first-degree relatives.2–4 These antibodies are found even years before the onset of clinical symptoms or detectable abnormalities of target-organ function.1–4 The present data indicate that AHAs precede echocardiographic abnormalities; AHA-positive relatives, classified as normal at first screening, progressed to DCM, LVE, or dFS. Thus, there is, in our opinion, good justification for equating the AHA-positive relatives in the present study with others diagnosed with noncardiac autoimmune disorders.2–4 The prospective data presented here are in keeping with earlier observations that revealed that these relatives have other features of immune activation.24,25
Relative Utility of Echocardiography and AHAs in DCM Family Studies
Prospective family studies indicate that echocardiographic abnormalities, defined as LVE and dFS, represent early, preclinical DCM or asymptomatic left ventricular dysfunction in symptom-free relatives,23 similar to the first-phase insulin response (FPIR) to intravenous glucose in prediabetes.29 Conversely, AHAs, similar to the multiple antibody markers in preclinical diabetes, precede other diagnostic abnormalities of heart dysfunction. In keeping with this, positive AHA status alone had higher sensitivity (61%) than its combination with abnormal echocardiogram (sensitivity 27%) as a predictor of progression to DCM, LVE, or dFS. In other words, positive AHAs with a normal echocardiogram identified a proportion of relatives at risk of progression to DCM, or of progression from normal to preclinical DCM (eg, LVE or dFS), that would not have been identified by echocardiography alone. In addition, the present data suggest that both techniques are necessary in DCM family screening and counseling. In fact, the positive predictive value (PPV) for progression to DCM was higher (18%) for both abnormal echocardiogram and positive AHAs than for AHAs alone (7%) or echocardiogram alone (10%). Similarly, the PPV for any progression (eg, DCM, LVE, or dFS) was higher (18%) for both an abnormal echocardiogram and positive AHAs than for AHAs alone (13%) or echocardiogram alone (10%). The combination of abnormal echocardiography and positive AHAs appears to identify relatives at a more advanced stage of preclinical DCM, who need closer follow-up and could potentially benefit from therapeutic intervention to attenuate or prevent disease development. Finally, negative AHAs alone or in combination with a normal echocardiogram had a good negative predictive value (98%) and allowed the identification of the majority of subjects at low risk of progression at least up to 5 years. An important issue that needs further study is the long-term outcome of these AHA-negative relatives with normal echocardiograms. In type 1 diabetes mellitus, a staging of preclinical disease has been proposed for siblings of affected children based on a combination of the initial number of antibodies and FPIR to intravenous glucose: no prediabetes (no antibodies), early prediabetes (1 antibody specificity, normal FPIR), advanced prediabetes (2 or more antibodies, normal FPIR), and late prediabetes (at least 1 antibody, reduced FPIR).29 By analogy, if the same applies to DCM, the staging could be as follows: no pre-DCM (negative AHAs, normal echocardiogram), early (positive AHAs, normal echocardiogram), advanced (AHA-positive and positivity for 1 or more of the other antibodies described in DCM13–22), and late pre-DCM (at least 1 antibody marker and LVE or dFS). Although 98% of relatives with negative AHAs and normal echocardiograms did not progress up to 5 years, a long latency period and slow progression are features of organ-specific autoimmune disease,1–4 and therefore, a proportion of them may develop AHAs in the future, thus becoming at risk. Therefore, longer follow-up is needed to completely reassure these subjects, and it may be appropriate to provide echocardiographic and immunologic testing, although less frequently than for those with AHAs and/or abnormal echocardiography.
Limitations of Cardiac Autoantibody Tests for Risk Assessment in DCM Family Studies
Several autoimmune features seen in DCM resemble those found in type 1A diabetes mellitus: male preponderance, human leukocyte antigen (HLA)-DR4 association,1,4,30 familial aggregation,1–6 familial clustering of other autoimmune diseases,1,31 and presence of multiple cardiac autoantibody specificities among patients and asymptomatic relatives.1–4,7,15–22,32 The detection of multiple autoantibodies or of a single high-titer antibody increases the PPV of autoimmune serology in siblings of type 1A diabetes mellitus.4,29,32 In addition, some of these markers appear early and are closely associated with the initial pathogenetic events, whereas others are detected later, in relation to epitope spreading; consequently, each antibody or antibody combination has distinct predictive value.33
Three of the autoantigens recognized by the AHA detected by indirect immunofluorescence in DCM were identified by our group as - and ß-myosin heavy chain and myosin light chain-1v by Western blotting.14 AHAs were not directed against tropomyosin, actin, or troponin, but other unknown antigens were present.14 The finding of disease-specific anti-myosin antibodies in myocarditis/DCM has been confirmed by others.15,16 Although myosin is one of the relevant antigens responsible for the AHAs detected by indirect immunofluorescence, Western blotting, or ELISA in DCM, it is unknown whether subjects classified as seronegative for 1 antibody are positive for another, which is the temporal sequence of appearance of the various antibodies (anti-myosin, troponin, ß-adrenoceptor, mitochondrial, and other antigens) and whether single or multiple antigen-specific antibody tests will be superior to a non–antigen-specific technique such as indirect immunofluorescence as screening tools.13–22 Collaborative work among laboratories testing the individual antibodies is warranted. Further work on IgG subclass20 and epitope mapping21 for the individual antibodies may lead to an improvement in the predictability of the various tests.13–22 In type 1A diabetes mellitus, standardization and quantification of islet cell antibody has been advantageous to refine its PPV, particularly in relation to high-titer antibody conferring additional risk.3 To date, this is the first study showing that AHAs identify symptom-free relatives at risk of DCM; the follow-up is relatively short, and the study was not initially planned to prospectively test AHAs as disease predictors. The low incidence of primary and secondary end points (n=13 and 26, respectively) may result in low precision to estimate effect size and low power to detect effects. Finally, there is no equivalent of Juvenile Diabetes Foundation (JDF) units3 for AHAs. Although high AHA titers were not associated with progression, the present study was not powered to perform quantitative analysis on end-point–titrated positive sera. Further quantitative work should be performed as soon as the number of progressors increases, to test the hypothesis that high-titer AHAs may confer higher risk.
Will genetic markers combined with AHAs increase prediction among relatives at risk of DCM? In type 1A diabetes mellitus, the predisposing HLA markers identify relatives at higher risk when used in conjunction with antibody testing.4,29 This strategy is useful to assess the risk at the individual level or to recruit high-risk subjects for intervention trials; conversely, because it usually leads to reduced sensitivity, autoantibodies alone are recommended as the first-line screening in siblings.4 A weak HLA-DR4 association has been reported in nonfamilial DCM,30 but there have been negative studies.6 Because DCM is genetically and etiologically heterogeneous,6,7 further studies are needed to evaluate the potential contribution of HLA to genetic susceptibility and risk prediction. We had shown,7 and confirmed here, that in 30% of pedigrees, AHAs are not found, whereas positive AHAs in the proband were associated with AHAs among relatives. This reinforces the issue of heterogeneity in DCM, although long-term follow-up might reveal that some relatives from non-AHA families will develop these markers. AHA was also weakly but not significantly associated with progression among relatives of AHA-negative probands. This may relate to the lower number of progressors in this subset analysis; negative AHAs in the proband may also reflect reduced titers with disease progression.13 Thus, extended follow-up is needed to clarify whether there is an AHA form and a non-AHA form of DCM.
The lack of a greater association of AHAs with disease progression in first- versus second-degree relatives may reflect failure to reach statistical significance due to the low number of progressors, but it may also relate to the fact that autoimmune diseases are not entirely genetically determined, because they are thought to result from a polygenic HLA and non-HLA–linked susceptibility and its interaction with the environment.1,34 However, single gene defects might account for DCM in some families, eg, as for type 1A diabetes mellitus in autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy families.35
In conclusion, the presence of organ-specific AHAs in asymptomatic relatives predicts development of DCM at 5 years and provides a noninvasive immune marker in 60% of familial and nonfamilial cases of DCM. PPV of AHA was low. PPV of autoantibodies in autoimmune disease is a function of many variables, in particular, prevalence of the disease in the population, type of autoimmune disease, at-risk population screened (eg, for type 1A diabetes mellitus, twins versus first-degree relatives versus schoolchildren), autoantibody specificity, titer and persistence or fluctuation during follow-up, genetic risk (HLA predisposing or protective haplotypes), and follow-up length, owing to the long latency period.2–4,29,32,33 Thus, an accurate comparison of AHA with other organ-specific autoantibodies is not feasible, at least at this stage. However, the PPV of AHA is similar to that of islet cell antibody alone in some populations at risk of type 1A diabetes mellitus.36 So far, evidence for a direct pathogenic role of AHA is lacking. The relatively high proportion of AHA relatives who did not progress in the mid term is likely to reflect the long latency period and slow progression of disease. Long-term prospective clinical and immunologic follow-ups are warranted.
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Acknowledgments |
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Sources of Funding
Drs Caforio, Baig, Murphy, Elliott, and McKenna were funded by British Heart Foundation grants or fellowships; Dr Caforio was funded by the Ministry of Health (MIUR), Rome, Italy, and the Veneto Region, Venice, Italy
Disclosures
None.
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