Postviral autoimmune heart disease--fact or fiction?
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Autoimmune Diseases↗
Biomedical subjects
A L Caforio
Publications and source records attributed to A L Caforio.
Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression.
OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up. METHODS: Antibody status was assessed by indirect immunofluorescence in 110 patients with dilated cardiomyopathy (85 male, mean (SD) age 44 (13) years) at diagnosis and at follow up (mean (SD) 14 (12) months); in 57 of them cardiac specific anti-alpha myosin antibody titres were also measured by an enzyme-linked immunosorbent assay (ELISA). Patients underwent complete evaluation at diagnosis and clinical and non-invasive assessment at follow up, including exercise testing with maximal oxygen consumption measurements. RESULTS: The frequency of cardiac specific antibodies by immunofluorescence was lower at follow up than at diagnosis (28 (25%) v 11 (10%), P = 0.002). Mean (SEM) anti-alpha myosin antibody titres at follow up were also lower than at diagnosis (0.24 (0.02) v 0.30 (0.02), P = 0.038); 24% of patients at diagnosis and 14% at follow up had an abnormal ELISA result. None of the patients who were negative by immunofluorescence or ELISA at diagnosis became positive at follow up. Presence of antibody at diagnosis was associated with milder symptoms and greater exercise capacity at follow up and persistence of antibody at follow up was associated with stable disease and milder symptoms at diagnosis. CONCLUSIONS: Cardiac specific autoantibodies in dilated cardiomyopathy become undetectable with disease progression; this is a recognised feature of other autoimmune conditions, such as type 1 diabetes. Detection of these antibodies at diagnosis and at follow up may provide a non-invasive marker of early dilated cardiomyopathy.
Adult↗
Autoimmunity in myocarditis and dilated cardiomyopathy: cardiac autoantibody frequency and clinical correlates in a patient series from Italy.
BACKGROUND: Organ- and disease-specific cardiac autoantibodies, detected by indirect immunofluorescence, represent markers of autoimmunity in a subgroup (25-35%) of patients with dilated cardiomyopathy or myocarditis from Northern Europe and the United States of America. Autoantibody frequencies, as well as associations between clinical and immunological features, may vary in patients from different countries, due to ethnically related differences in genetic susceptibility to autoimmune disease. METHODS: We assessed the frequency of cardiac autoantibodies in a series from Italy, including 91 subjects with idiopathic dilated cardiomyopathy (61 male, aged 49 +/- 11 years) and 11 with biopsy-proven (Dallas criteria) myocarditis (7 male, aged 23 +/- 16), including 2 cases of giant cell myocarditis. Controls were 160 patients with other cardiac disease, 141 with ischemic heart failure and 270 normals Cardiac antibody test was performed blindly by indirect immunofluorescence on normal human myocardium and skeletal muscle. RESULTS: The frequency of organ-specific cardiac autoantibodies was higher (p = 0.0001) in myocarditis (45%) and in dilated cardiomyopathy (20%) than in other cardiac disease (1%), in ischemic heart failure (1%), or in normals (2.5%). Cross-reactive antibodies were detected in similar proportions of study patients and controls. Both patients with giant cell myocarditis were antibody positive. Myocarditis patients with cardiac antibodies had shorter duration of symptoms compared to those who were antibody negative (0.4 +/- 0.3 vs 4 +/- 1 months, p = 0.004). In dilated cardiomyopathy, antibody status was not associated with any clinical or diagnostic feature. CONCLUSIONS: Autoimmunity is involved in a subset of patients with myocarditis and with dilated cardiomyopathy, regardless of their geographical origin or immunogenetic background. The antibody frequency in our dilated cardiomyopathy series from Italy tended to be lower than in other countries. This may reflect reduced antibody levels with disease progression and/or the recognised feature that Mediterranean populations are often less susceptible to autoimmune disease.
Acute Disease↗
Increased frequency of organ-specific cardiac antibodies in healthy relatives of patients with dilated cardiomyopathy: evidence for autoimmunity in Polish families.
BACKGROUND AND HYPOTHESIS: Autoantibodies represent markers of autoimmune involvement and are found with increased frequency in patients and their symptom-free relatives at risk compared with normal controls. Cardiac-specific autoantibodies, detected by immunofluorescence, were found in 20% of symptom-free relative of patients with dilated cardiomyopathy (DCM) from England and Italy. The role of autoimmunity may vary in DCM patients from Poland due to ethnic differences in genetic susceptibility to autoimmune disease. METHODS: We assessed the frequency of the organ-specific cardiac autoantibodies in 162 symptom-free relatives of DCM patients [85 male, mean (SD) age 27 (18) years] and 80 control subjects from Poland. Familial DCM (> 1 affected member) was present in 4 families, nonfamilial DCM in the remaining 24 pedigrees. We performed antibody screening and noninvasive cardiological assessment in the whole group. RESULTS: The frequency of cardiac-specific autoantibodies was higher among patients with documented DCM (probands and relatives) (50%) and their symptom-free relatives (38%) than in unrelated normal subjects (10%; p = 0.0001). In 24 (86%) of the pedigrees studied, autoantibodies were found in the proband and/or in at least one family member and tended to be more common in familial than in nonfamilial DCM (50 vs. 35%, p = NS). Echocardiographic indices of left ventricular size and function were similar in relatives with and without detectable antibodies. CONCLUSIONS: The presence of cardiac-specific autoantibodies in symptom-free relatives of DCM patients provides evidence for autoimmunity in the majority (86%) of our pedigrees, including both familial and nonfamilial forms of DCM.
Adolescent↗
Evidence for autoimmunity to myosin and other heart-specific autoantigens in patients with dilated cardiomyopathy and their relatives.
Autoimmune disease is characterised by the presence of circulating autoantibodies in the affected patients and in a proportion of their relatives. These antibodies are generally not pathogenic but are reliable markers of immune-mediated tissue damage. In organ-specific autoimmune disease, the destruction process is largely restricted to one organ within the body and the autoantibodies react with autoantigens which are unique to the diseased target organ. At least in a patient subset, myocarditis and dilated cardiomyopathy (DCM) may represent the acute and chronic stages of a progressive organ-specific autoimmune disease of the myocardium. Autoimmune features in patients with myocarditis/DCM include: familial aggregation, a weak association with HLA-DR4, abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy, and detection of organ- and disease-specific cardiac autoantibodies, by immunofluorescence and absorption techniques, in the affected patients and in a proportion of their symptom-free relatives from both familial and non-familial DCM pedigrees. The organ-specific cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. One of these, first identified using immunoblotting and confirmed by ELISA, is the cardiac-specific alpha-myosin isoform. Myosin fulfils the expected criteria for organ-specific autoimmunity, in that immunisation with cardiac but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of DCM; in addition, alpha-myosin is entirely cardiac-specific and is only expressed in the myocardium. Using ELISA, high titer organ- and disease-specific anti alpha-myosin antibodies have been found in 16% of the symptom-free relatives of DCM patients and in 38% of the pedigrees of the same cohort of relatives studied by immunofluorescence. The ELISA results provide additional evidence for autoimmunity in a subset of DCM families, and emphasise the importance of alpha-myosin as a target antigen.
Autoantibodies↗
Recognition and optimum management of myocarditis.
Myocarditis is a poorly understood condition and its prevalence is largely underestimated. A significant proportion of cases may be subclinical and chronic, leading to dilated cardiomyopathy, which represents the first cause of heart transplantation worldwide. Although inflammation of the myocardium can be associated with various causes, particularly viruses, myocarditis is usually idiopathic. Present evidence suggests that some 'idiopathic' and chronic 'postviral' myocarditis cases may be autoimmune, whereas others with acute self-limited disease or with persisting pathogenic virus by molecular methods may represent viral myocarditis. The major obstacle in identifying a specific therapy in myocarditis lies in the difficulty of a thorough clinical characterisation of individual patients in relation to viral and autoimmune involvement. This also explains the inconclusive results of trials of immunosuppressive drugs in myocarditis/dilated cardiomyopathy. Diagnosis is based upon endomyocardial biopsy. Management of myocarditis requires avoidance of agents that exacerbate myocarditis or depress myocardial function, and conventional therapy for heart failure (diuretics, ACE inhibitors and, if indicated, digoxin) and arrhythmias. Although at present the use of immunosuppressive therapy cannot be recommended on a routine basis, the recent Myocarditis Treatment Trial, where an aetiologically heterogeneous patient population was treated without significant adverse effects, provides some rationale for applying the same immunosuppression protocol to selected patients, e.g. those with active biopsy-proven myocarditis, unresponsive to conventional therapy, prior to transplantation, and those with idiopathic giant cell myocarditis.
Aging↗
Donor age greater than 50 years does not influence midterm results of heart transplantation.
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Adult↗
Evolution of focal moderate (International Society for Heart and Lung Transplantation grade 2) rejection of the cardiac allograft.
BACKGROUND: In the absence of clinical evidence of cardiac allograft rejection, it is still poorly defined whether the International Society for Heart and Lung Transplantation biopsy grade 2 (e.g., focal moderate rejection) should be treated. Aim of the present study was to retrospectively investigate the evolution of focal moderate rejection, diagnosed during the first postoperative year in patients who had undergone orthotopic heart transplantation. METHODS: A retrospective analysis was conducted on 256 International Society for Heart and Lung Transplantation grade 2 biopsies from 110 orthotopic heart transplantations; 125 episodes occurred within the first 3 months (group 1), 131 later (group 2). For each grade 2 diagnosis, two biopsies, one immediately before and one after, were analyzed and classified as follows: lower (grade 0 or 1), equal (grade 2), or higher (grade 3 or 4). RESULTS: Evolution of grade 2 rejection was to a lower grade in 66% of cases, an equal grade in 16.8%, and a higher grade in 17.2%, with differences between group 1 and 2 (higher: 25% versus 10%, respectively, p = 0.005). Episodes which progressed into higher grades occurred earlier compared with those which persisted or resolved (9.2 +/- 8.6 weeks versus 20.0 +/- 15.6, p < 0.001). Five-year actuarial survival and incidence of graft coronary disease were similar in patients whose conditions progressed and those whose conditions did not. However, left ventricular ejection fraction at 1 and 2 years was lower in patients whose conditions progressed compared with those whose conditions persisted or resolved (56% +/- 4% versus 66% +/- 2%, p = 0.004; 56% +/- 10% versus 64% +/- 8%, p = 0.02, respectively). CONCLUSIONS: Progression of grade 2 rejection occurred in a minority of cases and did not affect 5-year survival or incidence of coronary disease, but its relationship with long-term cardiac allograft dysfunction warrants further investigation.
Actuarial Analysis↗
Mid-term results of heart transplantation for end-stage valvular disease.
The results of heart transplantation in a consecutive series of 19 end-stage valvular disease patients (15 male, aged 48 +/- 8 years) were analysed retrospectively. The indication for heart transplantation was heart failure due to left and/or right ventricular dysfunction; 16 patients had undergone previous valve surgery, but prosthetic dysfunction was present in only one patient. All patients were in NYHA class IV, 15 were on oral anticoagulants and 5 on i.v. catecholamine support. There were four in-hospital deaths (21%) and one late death (5%), resulting in a 1-year mortality rate slightly, but not significantly, higher than that of patients transplanted for other indications (16%). Mean follow-up of the survivors was 48 +/- 33 months (range 9-95); 5-year actuarial survival was similar to that observed among the other heart transplantation patients (74 +/- 10% vs 77 +/- 3%, P = NS). The incidence of acute rejection and infection was also similar in valvular disease and non-valvular disease patients. Kidney and liver function at 1 year post-heart transplantation was preserved in all cases; cardiac catheterization revealed normal graft function in all patients and the absence of coronary lesions in all but two. In conclusion, in our limited experience morbidity and mortality in patients transplanted for end-stage valvular disease seem to be similar to those of patients undergoing heart transplantation for other etiologies.
Adult↗
Prognosis of idiopathic dilated cardiomyopathy.
Previous reports in referral populations have emphasized the poor prognosis of dilated cardiomyopathy. This study evaluated mortality and morbidity in patients presenting at a referral center between 1989 and 1993. One hundred seventy-two consecutive patients were studied. At presentation, 82 were in New York Heart Association functional class III/IV. Mean (+/- SD) left ventricular end-diastolic dimension was 69 +/- 11 mm, ejection fraction was 25 +/- 10%, VO2 max was 21 +/- 9 mL/min/kg, and sodium was 136 +/- 9 mM. Treatments included vasodilators (n = 157, 92%), anticoagulation (n = 50, 29%), amiodarone (n = 52, 30%), and cardiac defibrillator (n = 5, 3%). During the follow-up period (mean, 26 +/- 29 months), 16 patients died and 60 developed progressive heart failure; 46 (27%) required cardiac transplantation. The majority of the patients (102, 59%) were stable or improved. Established prognostic determinants (left ventricular end-diastolic dimension, ejection fraction, sodium, and arrhythmia) were of low predictive value for the development of progressive heart failure or sudden death. The 1- and 2-year probabilities of death or transplantation was 16 and 21%, respectively (death only 6 and 7%, respectively). These observations are subject to referral bias, but suggest that the majority of patients can remain stable. Any improvement in survival compared to earlier experience can be due to earlier diagnosis, availability of transplantation, and new heart failure management strategies.
Adolescent↗
Organ-specific cardiac autoantibodies in dilated cardiomyopathy--an update.
Autoimmune disease is characterized by the presence of organ- and disease-specific autoantibodies in patients and first degree relatives; antibody detection may precede disease onset by several years. We investigated potential involvement of organ-specific autoimmunity in dilated cardiomyopathy (DCM). Using indirect immunofluorescence and absorption studies, organ- and disease-specific IgG cardiac antibodies were found in one-third of DCM patients. Antibody status at diagnosis was associated with better exercise capacity; at 1-year follow-up two-thirds of antibody-positive patients became negative. These findings suggest that antibodies are early markers; their absence in the majority of patients at diagnosis may relate to long-standing pre-clinical DCM. Antibody screening was performed in asymptomatic DCM relatives, 177 from 33 families with > 1 affected individual (familial DCM) and 165 from 31 pedigrees with non-familial DCM. Antibodies were detected in 37 (58%) pedigrees and were more common among relatives than in normals (20% vs 3.5%, P = 0.0001). Antibody-positive relatives were younger, had larger left ventricular end-systolic dimension and reduced % fractional shortening compared to antibody-negative relatives. These findings provide evidence for autoimmunity in a subset (58%) including both familial and non-familial DCM; cardiac-specific antibodies may identify relatives at risk of developing DCM.
Adult↗
Organ-specific cardiac autoantibodies in dilated cardiomyopathy. Frequency and clinical correlates in Polish patients.
Organ- and disease-specific cardiac autoantibodies are found in a third of dilated cardiomyopathy patients from the U.K. and Italy and represent markers of autoimmune involvement. The role of autoimmunity may vary in dilated cardiomyopathy patients from different countries due to differences in genetic susceptibility to autoimmune diseases. The aim of this study was to assess the frequency of organ-specific cardiac autoantibodies detected by immunofluorescence in a consecutive series of patients with dilated cardiomyopathy and in disease and normal control subjects from Poland. The study groups included 79 patients with idiopathic (WHO criteria) dilated cardiomyopathy, 55 patients with other cardiac disease and 60 normal subjects. Cardiac antibody tests were performed by indirect immunofluorescence on human heart; skeletal muscle was used to identify cross-reacting antibodies. The frequency of organ-specific cardiac autoantibodies was higher in patients with dilated cardiomyopathy (21/79, 27%) than in controls with other cardiac disease (1/55, 2% P < 0.001) or in normal subjects (7/60, 12% P < 0.02). Conversely, cross-reactive antibodies were detected in similar proportions in patients with dilated cardiomyopathy (5/79, 6%), disease controls (7/55, 13%) and normal subjects (6/60, 10%, P = ns). The organ-specific antibody was more common in patients with dilated cardiomyopathy with insidious onset of disease (17/34, 50%) compared to those who did not exhibit this feature (4/45, 9%, P < 0.0001). Organ- and disease-specific cardiac autoantibodies were found in 27% of Polish patients with dilated cardiomyopathy at diagnosis; this is evidence for autoimmune involvement in a subset of patients from our country, as seen in a previously reported series of Western European origin. The association of antibody status with insidious onset of symptoms is in keeping with the long latency period observed in other autoimmune disorders.
Adult↗
Familial dilated cardiomyopathy in the United Kingdom.
OBJECTIVES: To determine the frequency and mode of inheritance of familial dilated cardiomyopathy in the United Kingdom. BACKGROUND: Two recent prospective studies have suggested that familial forms of dilated cardiomyopathy are common but have been limited by selective screening methods, inadequate diagnostic criteria, and low rates of ascertainment. METHODS: Prospective screening study of 236 relatives from 40 families of patients with dilated cardiomyopathy. Screening consisted of clinical examination, 12 lead electrocardiogram, and two-dimensional Doppler echocardiography. Relatives with systemic hypertension and other cardiac diseases were excluded from the study. All echocardiograms were performed by an experienced echocardiographer who was blinded to clinical information. Relatives were classified as having dilated cardiomyopathy, left ventricular enlargement (method of Henry), depressed fractional shortening, or as being normal. Relatives with abnormal investigations underwent further evaluation as appropriate. RESULTS: Twenty five cases of dilated cardiomyopathy were identified and came from 10 (25%) of the 40 families screened. Pedigree analysis was most consistent with autosomal dominant inheritance and variable penetrance (65-95%). Of the remaining apparently healthy relatives, 37 (18%) were found to have left ventricular enlargement and nine (4%) depressed fractional shortening; these values were significantly higher than those observed in 239 healthy controls (24 (10%), P = 0.02 and one (0.4%), P = 0.01, respectively). CONCLUSIONS: Patients with dilated cardiomyopathy commonly have an affected family member and a high proportion of apparently healthy relatives with minor echocardiographic abnormalities. Segregation analysis suggests that familial dilated cardiomyopathy is the result of the transmission of a rare autosomal dominant gene. Further studies are currently underway to characterise the molecular basis of familial dilated cardiomyopathy and identify early disease within these families.
Adolescent↗
Autoimmunity to alpha myosin in a subset of patients with idiopathic dilated cardiomyopathy.
OBJECTIVE: To use an enzyme linked immunoassay (ELISA) technique to assess frequency and disease specificity of anti-alpha-myosin antibodies in patients with dilated cardiomyopathy and their relatives. METHODS: Evaluation was performed on sera (dilution 1/320) from 123 consecutive patients with dilated cardiomyopathy (WHO criteria) (age 42 (SD 14) years), 252 of their relatives (35 (17) years), 203 healthy controls (45 (16) years), and 92 patients with ischaemic heart disease (63 (11) years). RESULTS: Abnormal antibody levels were commoner in patients with dilated cardiomyopathy (25, 20%) than in ischaemic heart disease (4, 4%), or normal controls (4, 2%, P = 0.001). Forty one (16%) of the relatives had abnormal results compared to the controls (4, 2%, P < 0.001) and antibodies were detected in 20 (38%) of pedigrees. Relatives from non-familial kindreds had higher antibody levels than those with familial disease (P << 0.001), and higher antibody levels were identified in 53 relatives of probands who had abnormal results compared to 116 relatives for whom the proband had a normal result (0.37 (SEM 0.02) v 0.22 (0.01); P < 0.001). CONCLUSIONS: The finding of anti-alpha-myosin antibodies in 20% of patients with dilated cardiomyopathy, in 16% of their asymptomatic relatives, and in 38% of families (particularly those with non-familial disease and where proband also had an abnormal result) provides additional evidence for autoimmunity against alpha myosin in a subset of patients.
Adult↗
Heart transplantation for end-stage valvular disease.
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Adult↗
Evidence from family studies for autoimmunity in dilated cardiomyopathy.
Organ-specific antibodies are found in patients with autoimmune disease and their symptom-free relatives many years before clinical onset. Organ-specific cardiac antibodies can be found in patients with dilated cardiomyopathy (DCM) and their relatives, which supports the idea that DCM is an autoimmune disease. We did non-invasive cardiological assessment and antibody screening in 342 symptom-free relatives (170 male, 172 female, mean [SD] age 31 [16] years). 177 relatives were from 33 families with more than 1 affected individual (familial DCM) and 165 relatives from 31 families with only 1 affected member (non-familial DCM). The frequency of cardiac antibodies was higher among relatives of DCM patients than in controls (20% vs 3.5%, p = 0.0001). In 37 (58%) of the families studied, cardiac antibodies were found in the proband and/or in at least 1 family member and were more common in familial than in non-familial DCM (24% vs 15%, p = 0.036). Antibody-positive relatives were younger (26 [15] vs 33 [17] years, p = 0.01) and had a larger mean echocardiographic left ventricular end-systolic dimension (35 [6] vs 32 [6], p = 0.01 mm) and reduced percentage fractional shortening compared with antibody-negative relatives (31 [6] vs 34 [6], p = 0.008). Presence of cardiac-specific autoantibodies in symptom-free DCM relatives provides evidence of autoimmunity in a subset of our patients (58%), including familial and non-familial forms of DCM. These antibodies are associated with mild left ventricular systolic dysfunction on echocardiography and may be early markers for relatives at risk of DCM.
Adult↗
A prospective case-control study of antibodies to coxsackie B virus in idiopathic dilated cardiomyopathy.
OBJECTIVES: This study was conducted to determine the frequency and significance of Coxsackie B virus-specific immunoglobulin-M (IgM) in patients with idiopathic dilated cardiomyopathy and compare them with the frequency in both unmatched and matched control subjects. BACKGROUND: The principal evidence supporting a pathoetiologic role for Coxsackie B viruses in human dilated cardiomyopathy is derived from retrospective serologic studies. These studies have evaluated patients with end-stage disease and have failed to recognize the importance of assessing both matched and unmatched control subjects. METHODS: In this prospective case-control study, we assessed sera for Coxsackie B virus-specific IgM (serotypes B1 to B5) from 114 patients with dilated cardiomyopathy at diagnosis or referral to our center, 94 healthy unmatched control subjects, 41 healthy matched control subjects from the same general practitioner and 32 members of the patients' own households. RESULTS: A higher frequency of positive Coxsackie B virus IgM was observed in patients with dilated cardiomyopathy than in unmatched control subjects (33% vs. 5%; p = 3 x 10(-7)). In patients with dilated cardiomyopathy, the response was monotypic (84%), commonly against serotypes B2 and B5, and was not associated with any clinical or histologic feature. The frequency of positive virus-specific IgM was similar in patients with dilated cardiomyopathy and their 41 matched community control subjects (46% vs. 27%; p = 0.11) and 32 household contacts (37% vs. 28%; p = 0.59). Control subjects who tested positive for virus-specific IgM tended more commonly to be seropositive than did control seronegative subjects (community control subjects 37% vs. 18%, p = 0.32; household contacts 42% vs. 20%; p = 0.36) and had an identical serotypic response in 4 (33%) of 12 cases. CONCLUSIONS: The frequency of Coxsackie B virus IgM was higher in patients with dilated cardiomyopathy than in unmatched control subjects but was similar in patients and control subjects who shared the same environment, indicating local spread of infection. The reason for the association between Coxsackie B virus IgM and dilated cardiomyopathy and its relevance to pathogenesis remain to be established.
Adult↗
Role of autoimmunity in dilated cardiomyopathy.
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Adult↗