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European Heart Journal Advance Access originally published online on May 9, 2007
European Heart Journal 2007 28(11):1326-1333; doi:10.1093/eurheartj/ehm076
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis

Alida L.P. Caforio1,*, Fiorella Calabrese2, Annalisa Angelini2, Francesco Tona1, Annalisa Vinci1, Stefania Bottaro1, Angelo Ramondo1, Elisa Carturan2, Sabino Iliceto1, Gaetano Thiene2 and Luciano Daliento1

1 Division of Cardiology, Department of Cardiological, Thoracic, and Vascular Sciences, University of Padova-Policlinico, Centro ‘V. Gallucci’, Via Giustiniani 2, 35128 Padova, Italy
2 Institute of Pathological Anatomy, University of Padua, Padua, Italy

Received 6 October 2006; revised 23 February 2007; accepted 8 March 2007; online publish-ahead-of-print 9 May 2007.

* Corresponding author. Tel: +3949 821 2348; fax: +3949 876 1764. E-mail address: alida.caforio{at}unipd.it

See page 1279 for the editorial comment on this article (doi:10.1093/eurheartj/ehm111)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aims: Myocarditis may be idiopathic, viral, and/or immune; frequency of these forms and prognosis are ill-defined. We aimed at identifying aetiopathogenetic and prognostic markers in myocarditis, including viral genome on endomyocardial biopsy (EMB) by polymerase chain reaction (PCR) and serum anti-heart autoantibodies (AHA).

Methods and results: We studied 174 patients, 110 males, aged 36 ± 18 years, median follow-up 23.5 months, range 10–54; 85 patients had active myocarditis and 89 borderline myocarditis (no diffuse or severe inflammation) (Dallas criteria). Serum AHA were detected by indirect immunofluorescence. PCR was used to detect virus. Six-year actuarial survival was 73%. AHA were found in 56% of patients and positive PCR in 26%. Univariate predictors of death/transplantation were young age, longer symptom duration, giant cell myocarditis, NYHA II–IV, positive PCR, presentation with LV dysfunction, clinical signs/symptoms of heart failure, and echocardiographic and haemodynamic indexes of cardiac dysfunction. By Cox univariate analysis, highest risk was conferred by clinical signs/symptoms of left (HR = 4.3, CI 1.7–10.8, P = 0.002) and right heart failure (HR 3.4, CI 1.5–7.3, P = 0.002).

Conclusion: In myocarditis, biventricular dysfunction at diagnosis was the main predictor of death/transplantation. AHA identified immune-mediated myocarditis in the majority of cases. Viral genome was a univariate predictor of adverse prognosis. Our approach of using AHA and positive PCR as aetiopathogenetic markers should help patient selection and recruitment in future studies on aetiological therapy.

Key Words: Cardiomyopathy • Myocarditis • Antibodies • Immunology


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
In a patient subset, myocarditis and dilated cardiomyopathy (DCM) represent the acute and chronic stages of an inflammatory myocardial disease, which may be idiopathic, viral, and/or autoimmune.1,2 Diagnosis of myocarditis is based on endomyocardial biopsy (EMB)1,2; prognostic significance of features at presentation is ill-defined and management is hampered by difficulties in establishing aetiopathogenesis.2–9

Polymerase chain reaction (PCR) on EMB tissue has become the gold standard for the diagnosis of viral myocarditis or cardiomyopathy.10–19 Some, but not all, studies suggested that positive PCR for virus may be an unfavourable predictor, and it has been proposed that additional prospective data are needed.7 Using indirect immunofluorescence (IFL), circulating organ- and disease-specific anti-heart autoantibodies (AHA) are detected, which represent non-invasive autoimmune markers in myocarditis and DCM.9,20–25 Prospective data in myocarditis patients characterized by viral PCR and AHA to identify distinct aetiopathogenetic subsets are lacking. This would be clinically relevant, as some studies suggest a favourable effect of aetiology-directed therapies.12,17,18,26

In this prospective study, we aimed at assessing aetiopathogenesis and prognostic relevance of features at diagnosis in myocarditis, including a positive PCR for virus and serum AHA as viral and autoimmune markers, respectively.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Patients
Study subjects were 174 consecutive patients (110 males, mean age 36 ± 18 years), admitted to our institution, a tertiary referral centre for arrhythmias and heart transplantation, from January 1992 to May 2005, with cardiac symptoms and clinical suspicion of myocarditis, in the absence of known non-inflammatory causes, including coronary artery disease. Patients were excluded if they did not give written informed consent to EMB; none refused to give consent. All patients underwent transthoracic Doppler echocardiography (TTE), complete heart catheterization, right ventricular (RV) EMB, and selective coronary angiography. TTE RV ejection fraction (RVEF) was calculated as described27; severe RV dilation was defined as RV end-diastolic volume >100 mL/m2 and severe RV dysfunction as RVEF <35%. The local Ethics Committee approved the study design and written informed consent was obtained for all patients.

Histology, immunohistology, and molecular analysis on endomyocardial biopsy
Three to five EMB samples from each patient were obtained and processed.2 Histological diagnosis was based on the Dallas criteria.28 Immunohistochemistry was used for the characterization of inflammatory infiltrates; cutoff for positive immunohistochemistry was that of an inflammatory infiltrate count ≥14 common leucocyte antigen positive cells/mm2.2 One or two frozen EMB specimens per patient were used for PCR and reverse transcriptase PCR analysis and for detection of cardiotropic viruses' genome.2,12,14–16 Patients were prospectively analysed for all viruses studied, except for Parvovirus B19 that started on year 2000. To exclude passive blood contamination, blood samples were collected for each patient at the same time of EMB and tested by PCR for the same virus in the presence of a positive result on EMB. The frequency of positive PCR in myocarditis was compared with that observed in RV EMB obtained during life, for diagnostic purposes or peri-operatively at the time of heart transplantation, in our established control groups of histopathologically confirmed non-inflammatory heart disease (n = 13, 11 males, age range 4–71 years, of whom five with restrictive cardiomyopathy, two with valvular heart disease, four with congenital heart disease, and two with amyloidosis), ischaemic heart disease (n = 17, 15 males, age range 44–56 years), and normal heart donors (n = 8, seven males, age range 33–56 years).14–16

Anti-heart autoantibodies testing by standard indirect immunofluorescence
For the detection of AHA, sera, available in 130 patients, were tested by standard IFL at one-tenth dilution on 4 µm thick unfixed fresh frozen cryostat sections of blood group O normal human atrium and skeletal muscle.9,20,21 The frequency of AHA in myocarditis was compared with that of our control groups of histopathologically confirmed non-inflammatory heart disease (n = 160, 80 males, aged 37 ± 17 years, of whom n = 55 rheumatic heart disease, n = 67 hypertrophic cardiomyopathy, and n = 38 congenital defects), ischaemic heart disease (n = 141, 131 males, aged 44 ± 14 years), and normal subjects (n = 270, 123 males, age 35 ± 11).9,20,21 Forty-one of the 141 ischaemic patients, aged 47 ± 12 years, 28 males, 31 in NYHA III and 10 in NYHA IV, had suffered a myocardial infarct 6 months to 10 years (median 2 years) previously; ejection fraction ranged from 16 to 44% (mean 30 ± 7).9,20,21

Follow-up
All patients were invited for follow-up at 3–6-month intervals at a dedicated outpatient clinic. Assessment included physical examination, 12-lead electrocardiogram, and TTE on each visit. Treatment did not include immunosuppressant, anti-viral, or immunomodulatory treatments.

Statistics
Results for quantitative features are given as mean ± SD or as median (interquartile range) for variables deviating from the normal distribution. Student's t-test, one-way analysis of variance, {chi}2 test, Fisher's exact test, or Kolmorogov–Smirnov test were used as appropriate. Endpoints/outcomes of interest during the follow-up period were death or heart transplantation. The Kaplan–Meier method was used to construct life tables of the likelihood of survival free from heart transplantation or death. Differences between actuarial curves were analysed by the Mantel–Haenszel log-rank test. Cox univariate analysis was used to assess associations between clinical and diagnostic features and survival to death or heart transplantation; results are expressed with the hazard ratios (HRs) and their associated 95% confidence intervals (CIs). All P-values were two-tailed; P-values less than 0.05 were considered to indicate statistical significance. All statistical analyses were performed using the SPSS software version 12.0 (SPSS, Inc., Chicago, IL, USA; 1998).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
Clinical features at presentation
Baseline features at presentation are detailed in Table 1. History of non-cardiac autoimmune disease was present in 9% of patients and allergy in 17%. Clinical presentation was with arrhythmia and/or syncope (19%, group I), symptomatic or asymptomatic LV and/or RV dysfunction (54%, group II), and chest pain at rest with abnormal cardiac enzymes (median troponin I levels of 8 ng/mL, interquartile range 1.5–20.6) and normal coronary arteries (27%, group III). Cardiac symptoms preceding hospital admission (median duration 0.5 months, interquartile range 0–3) were often reported; 86 patients were in NYHA class I, 51 in II, 30 in III, and seven in IV. NYHA distribution at diagnosis, shown in Table 1, was worse when compared with that prior to hospital admission (P = 0.001). Two patients presented with heart failure in the peri-partum. In addition to the ECG findings shown in Table 1, ST-T abnormalities in the absence of bundle branch block or LV hypertrophy were found in 69 (40%) patients: negative T waves in 42, of whom 11 with associated ST-elevation of non-ischaemic type, ST-elevation of non-ischaemic type only in 25, and ST-depression in two. On EMB, 85 patients had active and 89 borderline myocarditis in the absence of diffuse or severe inflammation (lymphocytic in 162, giant cell in five, and others in seven) (Figures 1 and 2).


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  		Table 1 Baseline features of the 174 myocarditis patients

 

Figure 1
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  		Figure 1 Active myocarditis: extensive inflammatory infiltrates, myocyte necrosis and fibrosis on endomyocardial biopsy (A and C: haematoxylin–eosin and B and D: Masson trichrome stain). Original magnification: x10. Insert: polymerase chain reaction analysis for parvovirus B19: line 1: DNA marker; line 2: endomyocardial biopsy positive for parvovirus B19; line 3: negative control (reagents without template); and line 4: parvovirus positive control.

 

Figure 2
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  		Figure 2 Borderline myocarditis: sparse lymphocytes without myocyte necrosis on endomyocardial biopsy (A and B: haematoxylin–eosin, magnification: x10 and x40, respectively). (C) and (D): immunohistochemistry for CD3. Magnification x10 and x30. PCR analysis was negative for viruses (data not shown).

 
Anti-heart autoantibodies and viral genome by polymerase chain reaction: frequency and clinical correlates by univariate analysis
AHA of IgG class were detected in 73 (56%) of the study patients: 54 (41%) of the organ-specific type and 19 (15%) of the partially organ-specific type (Figure 3). The frequency of organ-specific AHA was higher (P < 0.0001) in myocarditis (41%) than in non-inflammatory heart disease (1%), ischaemic heart disease (1%), or normal blood donors (2.5%). Similarly, the frequency of the partially organ-specific AHA was higher (P < 0.0001) in myocarditis (15%) than in non-inflammatory heart disease (4%), ischaemic heart disease (1%), or normal subjects (3%). The finding of positive family history of non-ischaemic heart disease (defined as the presence of one or more alive or dead family members with cardiomyopathy in the absence of documented coronary artery disease) was more frequent among AHA-positive myocarditis patients; the proportion of those with atrial fibrillation or non-sinus rhythm was higher and peak troponin I levels were non-significantly lower (Table 2).


Figure 3
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  		Figure 3 Blood group O normal human atrium (left panels) and skeletal muscle (right panels) stained with (A and B) an anti-heart autoantibodies-negative control serum from a normal subject. No myocyte or muscle staining is present. (C and D): a serum from a myocarditis patient, containing partially organ-specific anti-heart autoantibodies. A fine striational indirect immunofluorescence is visible on atrial tissue; skeletal muscle is weakly positive. (E and F): a serum from a myocarditis patient, containing organ-specific anti-heart autoantibodies. A diffuse cytoplasmic indirect immunofluorescence is visible on atrial myocytes, not on skeletal muscle. Magnification x400.

 

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  		Table 2 Associations with anti-heart autoantibodies and polymerase chain reaction status in myocarditis patients

 
The frequencies of viral genomes by PCR are detailed in Table 3. Overall, 31 (26%) of the 120 tested were virus-positive; five patients were positive for more than one virus. The frequency of PCR-positive samples was higher (P = 0.007) in myocarditis (26%) than in disease or normal control samples (0%). LV or RV failure was more frequent among PCR-positive patients; TTE–LV ejection fraction (LVEF) was lower and the LV stroke volume was non-significantly lower (Table 2).


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  		Table 3 Frequency of virus-positive patients by polymerase chain reaction

 
Of the 98 patients in whom combined PCR and AHA was available, myocarditis was classified as autoimmune (positive AHA and virus-negative PCR) in 48% of patients, viral (virus-positive PCR and negative AHA) in 9%, viral and immune (virus-positive PCR and positive AHA) in 12%, and idiopathic and/or cell-mediated (virus-negative PCR and negative AHA) in 31%.

Predictors of death or transplantation and survival curves
At follow-up (median duration 23.5 months, interquartile range 10–54), 124 patients were alive without being transplanted, 26 dead or transplanted, and 24 (14%) lost; 121 patients were in NYHA I/II and three in III, with LVEF of 56 ± 13%. Actuarial survival was 87% at 2 years, 80% at 3 years, and 73% at 6 years, respectively (Figure 4, left panel); actuarial survival was lower in group II patients (P = 0.0005) (Figure 4, right panel). Probability or survival was also lower in giant cell myocarditis (P = 0.004) (Figure 5, top panel) and among patients with a positive PCR (P = 0.02) (Figure 5, bottom panel). A positive PCR was more common among dead/transplanted (7/15, 47%) than alive without being transplanted patients (17/93, 18%, P = 0.01).


Figure 4
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  		Figure 4 Left panel: probability for myocarditis patients of remaining free from death or transplantation. Right panel: probability for myocarditis patients of remaining free from death or transplantation according to clinical presentation (log-rank test). Patients with heart failure presentation had a worse outcome when compared with those with infarct-like or arrhythmic onset.

 

Figure 5
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  		Figure 5 Top panel: probability for myocarditis patients of remaining free from death or transplantation according to histological type (log-rank test); patients with giant cell myocarditis had a lower probability of survival than those with active lymphocytic, borderline myocarditis, or other histological types (sarcoid, polymorphic, and oeosinophilic). Bottom panel: probability for myocarditis patients of remaining free from death or transplantation according to polymerase chain reaction result for virus (log-rank test); patients with positive polymerase chain reaction had a lower probability of survival than those with negative polymerase chain reaction.

 
Associations between clinical and diagnostic features and survival to death or heart transplantation by the Cox univariate analysis are detailed in Table 4. Predictors were young age, clinical signs/symptoms of left and right heart failure, presentation with LV dysfunction, NYHA II–IV, longer symptom duration, and echocardiographic and haemodynamic indexes of left and right heart dysfunction. Highest risk was conferred by clinical signs/symptoms of left (HR = 4.3, CI 1.7–10.8, P = 0.002) and right heart failure (HR 3.4, CI 1.5–7.3, P = 0.002).


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  		Table 4 Associations between clinical and diagnostic features and survival to death or heart transplantation in myocarditis patients by the Cox univariate analysis

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
Prognostic relevance of clinical and diagnostic features at presentation
This prospective study provides evidence for the unfavourable prognostic value of left and right heart dysfunction at presentation in biopsy-proven myocarditis. RV dysfunction at diagnosis may reflect a greater severity of myocarditis in the RV, and/or its higher susceptibility to viral and/or immune-mediated damage.29 RV dysfunction is also a powerful predictor of adverse prognosis in advanced heart failure secondary to ischaemic or non-ischaemic DCM.30

In our study, as in other reports,4,31 the proportion (27%) of dead or transplanted patients at 6 years is high.4,31 Thus, biopsy-proven myocarditis should be regarded as a potentially ominous disease, particularly in the young presenting with LV and/or RV failure, and should lead to closer follow-up and prompt diagnosis by EMB.2,12,27,32 We observed no EMB-related complications. The adjunct of immunohistochemistry to the histological Dallas criteria, as confirmed here, enhances the sensitivity of EMB; more than half of our patients, with a Dallas diagnosis of borderline myocarditis, would have not been unequivocally diagnosed in the absence of immunohistochemistry. All of them fulfilled the recognized immunohistochemical cutoff of ≥14 common leucocyte antigen positive cells/mm2.2 Only four of our 174 patients fell into the previous definition of ‘fulminant’ myocarditis,4 and of these, three had giant cell and one peri-partum myocarditis. McCarthy et al.4 excluded both forms from their analysis. This may be misleading because, as reported3 and confirmed here, giant cell myocarditis has a worse outcome when compared with other histological types.

Viral genomes at presentation and prognosis
In our study, a positive PCR for virus was a univariate predictor of adverse prognosis. Our results are among the first prospective data in adult myocarditis diagnosed according to the World Health Organization definition (e.g. the Dallas histological criteria with the adjunct of immunological and immunohistochemical criteria).1,28

In keeping with others,10–13,18,19 we found that the frequency of positive PCR in myocarditis was higher (26%) than in the controls (0%), supporting a causative association in adults. As far as the frequencies of the individual viruses are concerned, these have been highly variable.7,10–14,18,19,33 Many factors may influence these figures: age (paediatric vs. adult), ethnicity, geographic and temporal variations in the epidemiology of viral infections, duration of symptoms in relation to the timing of EMB, number of EMB samples tested by PCR, and the use of autopsy myocardium rather than frozen EMB.7 This prevents us from drawing any epidemiological conclusion. The number of samples tested by PCR was lower in our study than in some,32,34,35 but not all, previous studies.10,18,19 Recent cross-sectional studies, reporting a much higher frequency of positive PCR for one or more viruses, were in patients with idiopathic LV dysfunction32 or LV diastolic dysfunction in the absence of myocarditis,34 thus their findings are not comparable with our study.

Anti-heart autoantibodies status at presentation and prognosis
We found AHA in a high proportion (56%) of myocarditis patients; the low frequency in controls and the association of AHA with family history for cardiomyopathy are in keeping with what is observed in other autoimmune diseases.36,37 AHA are more often detected in the acute phase of myocardial inflammation than in the chronic stage, e.g. DCM.9,20,22,23 AHA in DCM are associated with ‘early’ disease,20 and their titres become reduced with disease progression22; further, AHA are present in asymptomatic relatives, years before any echocardiographic abnormality.21,36 Thus, present evidence suggests that AHA represent early markers. Autoimmune myocarditis, identified by positive AHA and negative PCR, was the most common form (48%), suggesting that a majority of patients may benefit of immunosuppression. No aetiopathogenetic markers were used in the Myocarditis Treatment trial, producing negative results in relation to the role of immunosuppression.8 Conversely, recent studies suggest their beneficial effects in immune-mediated myocardial disease, identified by HLA up-regulation on EMB or serum AHA,12,26 in keeping with its efficacy in non-cardiac autoimmune disease.37 A prospective randomized trial, recruiting AHA positive and PCR negative patients for immunosuppression, is warranted.

In this study, 31% of cases were negative for both AHA and PCR. These might be classified as ‘idiopathic myocarditis’ and could reflect viral myocarditis, owing to yet unknown pathogens, or, most likely, a cell-mediated autoimmune form37 that might also benefit of immunosuppression. AHA occurred in association with positive PCR for virus in 12% of patients. These patients might be candidates for anti-viral and, after virus clearance, immunosuppression or combined anti-viral and immunosuppressive therapy.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
In biopsy-proven myocarditis, biventricular dysfunction at diagnosis was the main unfavourable predictor. AHA identified immune-mediated myocarditis in the majority of cases. Viral genome was a univariate predictor of adverse prognosis. Our approach of using AHA in conjunction with PCR to identify aetiopathogenesis in the individual subject should set the basis for patient characterization and recruitment in future studies on aetiological therapy.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
This study was supported by the MURST Target Projects (1999–2000, Myocarditis: therapeutic impact of aetiological diagnosis based upon molecular and immunological findings; 2003–2005, Myocarditis: identification of clinical, molecular, and immunological markers for risk stratification) and the Ministry of Health Target project (2004–2007, Inflammatory cardiomyopathy), Rome, Italy.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

  1. Richardson P, McKenna WJ, Bristow M, Maisch B, Mautner B, O'Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P. Report of the 1995 WHO/ISFC task force on the definition and classification of cardiomyopathies. Circulation (1996) 93:841–842.[Free Full Text]
  2. Angelini A, Crosato M, Boffa GM, Calabrese F, Calzolari V, Chioin R, Daliento L, Thiene G. Active versus borderline myocarditis: clinicopathological correlates and prognostic implications. Heart (2002) 87:210–215.[Abstract/Free Full Text]
  3. Cooper LT, Berry GJ, Shabetai R. Idiopathic giant cell myocarditis—natural history and treatment. N Engl J Med (1997) 336:1860–1866.[Abstract/Free Full Text]
  4. McCarthy RE, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, Baughman KL. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med (2000) 342:690–695.[Abstract/Free Full Text]
  5. Cappola TP, Felker GM, Kao WHL, Hare JM, Baughman KL, Kasper EK. Pulmonary hypertension and risk of death in cardiomyopathy. Patients with myocarditis are at higher risk. Circulation (2002) 105:1663–1668.[Abstract/Free Full Text]
  6. Mendes LA, Dec GW, Picard MH, Palacios IF, Newell J, Davidoff R. Right ventricular dysfunction: an independent predictor of adverse outcome in patients with myocarditis. Am Heart J (1994) 128:301–307.[CrossRef][ISI][Medline]
  7. Magnani JW, Dec W. Myocarditis.Current trends in diagnosis and treatment. Circulation (2006) 113:876–890.[Free Full Text]
  8. Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE, the Myocarditis Treatment Trial Investigators. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med (1995) 333:269–275.[Abstract/Free Full Text]
  9. Caforio ALP, Goldman JH, Haven AJ, Baig KM, Dalla Libera L, McKenna WJ. Circulating cardiac autoantibodies as markers of autoimmunity in clinical and biopsy-proven myocarditis. Eur Heart J (1997) 18:270–275.[Abstract/Free Full Text]
  10. Grumbach IM, Heim A, Pring-Akerblom I, Vonhof S, Hein WJ, Muller G, Figulla HR. Adenoviruses and enteroviruses as pathogens in myocarditis and dilated cardiomyopathy. Acta Cardiol (1999) 54:83–88.[ISI][Medline]
  11. Why HJ, Meany BT, Richardson PJ, Olsen EGJ, Bowles NE, Cunningham L, Freeke CE, Archard LC. Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation (1994) 89:2582–2589.[Abstract/Free Full Text]
  12. Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation (2003) 107:857–863.[Abstract/Free Full Text]
  13. Fujioka S, Kitaura A, Deguchi H, Kawamura K, Isomura T, Suma H, Shimizu A. Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol (2000) 36:1920–1926.[Abstract/Free Full Text]
  14. Calabrese F, Valente M, Thiene G, Angelini A, Testolin L, Biasiolo MA, Soteriou B, Livi U, Palu' G. Enteroviral genome in native hearts may influence outcome of patients who undergo cardiac transplantation. Diagn Mol Pathol (1999) 8:39–46.[CrossRef][ISI][Medline]
  15. Calabrese F, Carturan E, Chimenti C, Pieroni M, Agostini C, Angelini A, Crosato M, Valente M, Boffa GM, Frustaci A, Thiene G. Overexpression of TNF-{alpha} and TNF receptor-{alpha} I in human viral myocarditis: clinicopathologic correlations. Mod Pathol (2004) 17:1108–1118.[CrossRef][ISI][Medline]
  16. Calabrese F, Angelini A, Thiene G, Basso C, Nava A, Valente M. No detection of enteroviral genome in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy. J Clin Pathol (2000) 53:382–387.[Abstract/Free Full Text]
  17. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation (2003) 107:2793–2798.[Abstract/Free Full Text]
  18. Bowles NE, Ni J, Kearney DL, Pauschinger M, Schultheiss HP, McCarthy R, Hare J, Bricker JT, Bowles KR, Towbin JA. Detection of viruses in myocardial tissues by polymerase chain reaction: evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol (2003) 42:466–472.[Abstract/Free Full Text]
  19. Figulla HR, Stille-Siegerer M, Mall G, Heim A, Kreuzer H. Myocardial enterovirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy. J Am Coll Cardiol (1995) 25:1170–1175.[Abstract]
  20. Caforio ALP, Bonifacio E, Stewart JT, Neglia D, Parodi O, Bottazzo GF, McKenna WJ. Novel organ-specific circulating cardiac autoantibodies in dilated cardiomyopathy. J Am Coll Cardiol (1990) 15:1527–1534.[Abstract]
  21. Caforio ALP, Keeling PJ, Zachara E, Mestroni L, Camerini F, Mann JM, Bottazzo GF, McKenna WJ. Evidence from family studies for autoimmunity in dilated cardiomyopathy. Lancet (1994) 344:773–777.[CrossRef][ISI][Medline]
  22. Caforio ALP, Goldman JH, Baig MK, Haven AJ, Dalla Libera L, Keeling PJ, McKenna WJ. Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression. Heart (1997) 77:62–67.[Abstract/Free Full Text]
  23. Neumann DA, Burek CL, Baughman KL, Rose NR, Herskowitz A. Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy. J Am Coll Cardiol (1990) 16:839–846.[Abstract]
  24. Caforio ALP, Grazzini M, Mann JM, Keeling PJ, Bottazzo GF, McKenna WJ, Schiaffino S. Identification of {alpha} and ß myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation (1992) 85:1734–1742.[Abstract/Free Full Text]
  25. Lauer B, Schannwell M, Kuhl U, Strauer BE, Schultheiss HP. Antimyosin autoantibodies are associated with deterioration of systolic and diastolic left ventricular function in patients with chronic myocarditis. J Am Coll Cardiol (2000) 35:11–18.[Abstract/Free Full Text]
  26. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J. Randomized, placebo controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy. Two-year follow-up results. Circulation (2001) 104:39–45.[Abstract/Free Full Text]
  27. Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G, Malacrida S, Settimo L, Danieli GA, Thiene G, Nava A. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J (2005) 26:1666–1675.[Abstract/Free Full Text]
  28. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, Olsen EG, Schoen FJ. Myocarditis: a histopathological definition and classification. Am J Cardiovasc Pathol (1987) 1:3–14.[Medline]
  29. Matsumori A, Kawai C. Coxsackie virus B3 perimyocarditis in BALB/c mice: experimental model of chronic perimyocarditis in the right ventricle. J Pathol (1980) 131:97–106.[CrossRef][ISI][Medline]
  30. Brieke A, DeNofrio D. Right ventricular dysfunction in chronic dilated cardiomyopathy and heart failure. Coron Artery Dis (2005) 16:5–11.[CrossRef][ISI][Medline]
  31. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med (2000) 342:1077–1084.[Abstract/Free Full Text]
  32. Kuhl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction. Circulation (2005) 111:887–893.[Abstract/Free Full Text]
  33. Pankuweit S, Moll R, Baandrup U, Portig I, Hufnagel G, Maisch B. Prevalence of the parvovirus B19 genome in endomyocardial biopsy specimens. Hum Pathol (2003) 34:497–500.[CrossRef][ISI][Medline]
  34. Tschope C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck PL, Pauschinger M, Poller W, Kuhl U, Kandolf R, Schultheiss HP. High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation (2005) 111:879–886.[Abstract/Free Full Text]
  35. Kuhl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W, Schultheiss HP. Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation (2005) 112:1965–1970.[Abstract/Free Full Text]
  36. Caforio ALP, Mahon NG, Baig KM, Tona F, Murphy RT, Elliott PM, McKenna WJ. Prospective familial assessment in dilated cardiomyopathy. Cardiac autoantibodies predict disease development in asymptomatic relatives. Circulation (2007) 115:76–83.[Abstract/Free Full Text]
  37. Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky's postulates revisited). Immunol Today (1993) 14:426–428.[CrossRef][ISI][Medline]

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