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(Circulation. 2001;104:39.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy
Two-Year Follow-Up Results
yna Glanowska, MD
aw Wilczewski, MD
ski, MD, PhDFrom the Silesian Center of Heart Disease, Zabrze, Poland (R.W., T.N., M.Z., L.P.); the Second Department of Cardiology, Silesian Medical School, Zabrze, Poland (E.N.-K., C.W., G.G., P.W., J.W.); and the University of Texas Health Science Center, San Antonio, Tex (M.M.R.).
Correspondence to Romuald Wojnicz, MD, Silesian Center of Heart Disease, 41800 Zabrze, Szpitalna 2, Poland. E-mail wojnicz{at}dom.zabrze.pl
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionsReferences |
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Background—Previous studies have shown disappointing results for immunosuppressive treatment in patients with dilated cardiomyopathy. Therefore, we studied the effectiveness of such therapy in patients with HLA upregulation on biopsy.
Methods and Results—Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either immunosuppression or placebo for 3 months; they were then followed for 2 years. After 2 years, there were no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission) between the 2 study groups (22.8% for the immunosuppression group and 20.5% for the placebo). The secondary efficacy end point included changes in ejection fraction, end-diastolic diameter, end-diastolic volume, end-systolic volume and NYHA class; left ventricular ejection fraction increased significantly in the immunosuppression group compared with the placebo group (95% CI, 4.20 to 13.12; P<0.001) after 3 months of follow-up. The early favorable effects of immunosuppressive therapy on left ventricular volume, left ventricular diastolic dimension, and New York Heart Association class were also present. This improvement was maintained in the immunosuppression group at 2 years (ejection fraction: 95% CI, 6.94 to 19.04; P<0.001). In addition, on the basis of the protocol-specified definition of improvement, 71.8% patients in the immunosuppression group versus 20.9% patients in the placebo group met the criteria of improvement after 3 months (P<0.001). At the end of the follow-up period, 71.4% patients from the immunosuppression group versus 30.8% patients from the placebo group were improved (P=0.001).
Conclusions—These data demonstrate a long-term benefit of immunosuppressive therapy in patients with dilated cardiomyopathy and HLA upregulation on biopsy specimens. Thus, restoration of immunosuppressive therapy for such patients should be considered.
Key Words: cardiomyopathy • myocarditis • heart failure • immunohistochemistry • HLA antigens
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Dilated cardiomyopathy is not a single disease but a heterogeneous group of disorders that includes idiopathic, immune, and specific cardiomyopathy.1 Myocarditis, regardless of its pathogenesis, is thought to be a main cause of dilated cardiomyopathy.2 Unfortunately, the onset of disease may be asymptomatic, and its first manifestation is often heart failure.3 4 Although in many cases, the cause of myocarditis remains unknown, numerous factors can cause myocardial inflammation, including infections, toxic injuries, etc.5 Although some patients with myocarditis recover spontaneously and completely, a few may progress into chronic inflammatory heart disease, which presents clinically in many cases as inflammatory dilated cardiomyopathy.6 7
The diagnosis of myocarditis is based on histopathological criteria defined by the presence of inflammatory cellular infiltration and myocardial necrosis.8 The diagnosis is hampered by the focal nature of the disease and, despite multiple biopsies, sampling error still occurs.9 10 Although the Dallas criteria are an invaluable aid in myocarditis diagnosis, they are only as good as a specimen allows and they are often not sensitive enough to make an accurate diagnosis. Moreover, histology alone cannot readily distinguish between different forms of the disease, such as acute or chronic autoimmune myocarditis.10 11 Unlike histological features of myocarditis, which tend to be focal, immunohistological markers of inflammation (ie, upregulation of HLA) are distributed throughout the entire myocardium; therefore, a false-negative diagnosis would be less likely.11 In addition, autoimmunity, regardless of the trigger, has been strongly implicated in the pathogenesis of chronic inflammatory myocardial disease.12 13 14
The treatment of myocarditis is still problematic, and attempts to treat it with nonselective anti-inflammatory therapy remain controversial.15 16 17 Because the first randomized trial of immunosuppressive treatment for idiopathic dilated cardiomyopathy by Parrillo and coworkers,15 which was based on clinical enrollment for treatment, did not find that such therapy was efficacious, we tried to find new criteria that would enable us to select patients with inflammatory dilated cardiomyopathy who were potentially better responders for such therapy than those randomized previously. We hypothesized that the qualification of patients for immunosuppressive treatment should be based on an immunohistological evaluation of an endomyocardial biopsy instead of a clinical and/or histopathology diagnosis. Accordingly, in this prospective, randomized study, we used the increased expression of HLA in cardiac biopsy specimens to select patients for treatment. Thus, we studied 84 patients with immunohistologically verified chronic myocarditis who were randomly selected for treatment with or without immunosuppression in addition to conventional therapy.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Patient Enrollment
Enrollment took place from January 15, 1995, through October 30, 1997. The study population consisted of 202 patients with chronic heart failure due to dilated cardiomyopathy. All of them underwent endomyocardial biopsies. Eighty-four patients with the strong expression of HLA in biopsy specimens were randomized to placebo or immunosuppressive therapy. Among them, 31 patients with a history suggestive of ischemic heart disease or
2 standard
risk factors for atherosclerosis underwent
coronary angiography. Chronic heart failure was defined as
dyspnea or fatigue at rest or exertion for 6 months in association
with an ejection fraction (EF) 
40%. The EF was assessed by
echocardiography and radionuclide ventriculography.
Clinical characteristics of the patients are summarized in
Table 1
. The main exclusion criterion was lack of increased
expression of HLA molecules in the biopsy. The remaining exclusion
criteria included recent (<6 months) onset of systolic heart
failure, all known causes of heart failure (such as hypertension,
significant coronary artery disease, valvular heart
disease [but not relative mitral regurgitation],
endocrine disease, significant renal disease, drug or alcohol abuse,
and therapy with steroids within 6 months before the study). The
baseline clinical assessment included physical examination, ECG,
24-hour ECG monitoring, echocardiography,
radionuclide ventriculography, and coronary
angiography.
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The local human studies committee of the Silesian School of Medicine, Katowice, Poland, approved the protocol. Written informed consent was obtained from all study patients.
Therapy
All patients received conventional therapy, which
included digitalis, diuretics (furosemide 40 to 80 mg/d and
spironolactone 100 mg/d), an ACE inhibitor (captopril 50 to
75 mg/d), ß-blockers (metoprolol tartrate [Metocard], 50 to
100 mg/d), nitrates, an antiarrhythmic drug (amiodarone hydrochloride
[Cordarone], 200 to 400 mg/d), and bed rest. Patients were randomized
to placebo or immunosuppressive therapy with steroids and azathioprine
added to conventional therapy. Prednisone was started at a dose of 1 mg
· kg–1 ·
d–1 . After 12 days, the dose was tapered
off every 5 days by 5 mg/d until reaching the maintenance dose
of 0.2 mg · kg–1 ·
d–1 for a total of 90 days. Azathioprine
was given at a dose of 1 mg · kg–1 ·
d–1 for a total of 100
days.
Noninvasive Evaluation
Complete M-mode, 2D, and Doppler
echocardiographic examinations were performed with a
2.5 MHz transducer using a Hewlett-Packard SONOS
1000. EF was calculated in a standard manner and was used to
assess left ventricular systolic function. Left
ventricular end-diastolic diameter (EDD,
mm) was measured from the M-mode recordings, as recommended by
the American Society of Echocardiography. Left
ventricular end-diastolic volume (EDV) and
end-systolic volume (ESV) were obtained from the apical 4- and
2-chamber views by the modified Simpson’s method. Echocardiograms
(on-line and off-line) were assessed by 2 experienced investigators
independently (interobserver variability was <8%). Final assessment
was made by consensus. In addition, EF by
echocardiography was verified by radionuclide
ventriculography with technetium-99 m. The New York Heart
Association (NYHA) class was used to assess functional
capacity.
Invasive Evaluation and
Endomyocardial Biopsy
Patients with suspected coronary artery
disease underwent coronary angiography. Patients with any
significant lesion (>50% stenosis) were excluded from this
study. A right ventricular
endomyocardial biopsy was performed using a
Cordis bioptome. A minimum of 5 specimens were
obtained. Routinely, 4 specimens were used for
histological evaluation and 2 were used for
immunohistology. Tissue for immunohistochemistry, after embedding in
medium (OCT compound, Miles Inc), was
snap-frozen in liquid nitrogen. Histopathological evaluation of biopsy
specimens was performed according to the Dallas
criteria.9 This evaluation
was not taken into account for therapeutic
decision-making.
Immunohistological
Study
Acetone-fixed frozen sections (5 µm thick) were
incubated with mouse monoclonal anti-human antibodies (HLA-ABC [clone
W6/32; MHC class I] and HLA-DR, 
chain [clone TAL.1B5; MHC class
II)] from DAKO. HLA-DR antibodies were diluted
1:200, but HLA-ABC were diluted 1:400 in Tris-buffered saline (pH 7.6).
The streptavidin-biotin method (DAKO LSAB+
Kit/alkaline Phosphatase Detection system/New Fuchsin Substrate System)
was used according to the manufacturer’s instructions. The primary
antibody was omitted from negative control slides. As a positive
control, liver biopsy specimens from patients with chronic active
hepatitis were used. The immunohistological examination
of biopsy specimens was made by 2 investigators independently; each was
blinded to clinical features and histopathological diagnosis. The
interobserver variability was <2%. Each specimen was evaluated
qualitatively (intensity of staining) and semiquantitatively (scoring
system). The semiquantitative scoring system was defined
previously.18 For the
purposes of this study, staining 2 of one or both classes of HLA was
considered positive.
Follow-Up, End Points, and Definition of
Improvement
The effectiveness of therapy was assessed at the
times for follow-up (3, 6, 12, and 24 months) after the treatment. The
2-year follow-up was designed for final assessment of long-term
treatment efficacy.
Cardiac death, heart transplantation, and readmission to the hospital constituted the composite primary efficacy end point. The predefined, secondary efficacy end point included changes in EF, EDD, EDV, and ESV and changes in NYHA score, analyzed separately .
In addition to end point efficacy, patients were classified
as improved if they met an increase of >5 percentage points in the
absolute EF and had 2 selected criteria, such as decrease of EDV,
ESV, or EDD 10% and 1 class decrease in NYHA class compared with
baseline measures.
Statistics
The number of patients enrolled in this 2-center
trial was based on the results of previous studies on a related
subject.16 The baseline
characteristics of the treated groups were compared by Student’s
t test for continuous
variables and the Mann-Whitney U test or Fisher’s exact test for
categorical data. Normally distributed data are described with mean and
SD, but non-normally distributed data are presented as median
and interquartile range.
Changes in the primary and secondary end points were analyzed in the following 2 ways. (1) An intention-to-treat analysis with the 2-tailed Fisher’s exact test included all randomized patients (except patients who withdrew) for all follow-up end points. This test was also used to compare the proportions of patients who improved, as defined by the protocol. Patients who died, underwent heart transplantation, and/or were readmitted to the hospital were classified as unimproved. (2) A carry-forward analysis excluded patients who were lost to follow-up and who achieved the primary end point, and data were analyzed by Student’s t test for between-group comparisons and by 2-way (group effect and time effect) repeated measures ANOVA. In addition, for group comparisons in terms of changes in the values of measures (EF, EDV, ESV, EDD, and NYHA score), a Mann-Whitney U test and median test were used. This comparison was made only for patients who completed the 2-year follow-up period. Death and heart transplantation were also analyzed by log-rank test for event-free survival analysis. Statistical significance was accepted at the 95% confidence interval (P<0.05). Statistical analysis was made using SPSS version 9.01 software.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Patient Population
Patient demographic details are shown in Table 1
. Of the 84 patients included in the present
study, 43 were in the placebo and 41 were in the immunosuppressive
group. Normal coronary arteries and no evidence of
coronary spasm were demonstrated in all patients; 31 of the 84
patients (36.9%) underwent coronary angiography. Ten of the 84
patients (11.9%) dropped out during the follow-up period; 9 patients
withdrew because of poor compliance, and one patient withdrew because
of a change of his place of residence. Five of the 84 patients (5.9%)
died, 6 patients (7.1%) underwent heart transplantation, and 5 (5.9%)
were readmitted to the hospital during the 2-year period. Final
assessment was performed in 58 of the 84 patients (69%) who completed
the treatment and follow-up; 30 patients were in the placebo group, and
28 were from the immunosuppression group. Patients were in NYHA
functional class II (n=23; 27.4%), III (n=55; 65.5%), and IV (n=6;
7.1%).
On the basis of Dallas criteria, 7 patients (8.3%) had
active myocarditis, 16 (19%) had borderline myocarditis, and 61
(72.6%) had no myocarditis
(Table 1). Upregulation of HLA class I (ABC antigens) was
present in all randomized patients
(Figure 1A). The de novo induction of HLA-ABC antigens on
cardiac myocytes was detected in 76 patients (90.5%;
Figure 1B). Increased expression of HLA class II
(Figure 1C) was found in 68 patients (80.9%), but the
induction of these molecules on the cardiac sarcolemma was detected in
only 5 cases (5.9%). The remaining 11 patients (13.1%) had normal
HLA-DR expression
(Figure 1D).
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Follow-Up and Primary Efficacy End
Point
Two patients from the immunosuppression group did not
complete the treatment and were lost to follow-up. None of the
remaining patients achieved the primary end point at 3 months. After 6
months, 4 patients (2 patients in both groups) were lost to follow-up.
The primary end point was less common in patients in the
immunosuppression group compared with those in the placebo group (2
versus 5 cases), but this difference was not statistically significant.
After 1 year, 4 more patients withdrew from the study (2 patients in
both groups). At this time, the primary end point occurred in 4 of the
33 patients from the immunosuppression group (12.1%) and 3 of the 39
patients in the placebo group (7.7%). At 2 years, the primary end
point occurred in 2 of 35 patients (5.7%) from the immunosuppression
group and none of those in the placebo group. The immunosuppression and
placebo groups did not differ significantly in the primary efficacy end
point at the end of follow-up (8 of 35, 22.8% for immunosuppression
versus 8 of 39, 20.5% for placebo;
P=NS by log-rank test for
event-free survival analysis).
Secondary Efficacy End Point
Results are displayed for the secondary end point in
Table 2 and
Figure 2. No significant difference was noted in baseline
values, although there was a trend for higher ventricular
volumes among the placebo group. Immunosuppressive therapy was
associated with significant early improvement. By the carry-forward
analysis, mean EF increased significantly in the
immunosuppression group compared with the placebo group (95% CI, 4.2
to 13.1; P<0.001). Secondary
end points for left ventricular volumes and EDD decreased
significantly in the immunosuppression group. The favorable effect of
immunosuppressive therapy on NYHA class was also present, but it
was not statistically significant
(P=0.097). The increase in the
mean EF achieved by month 3 was maintained in the immunosuppression
group compared with the placebo group after 6 months of follow-up (95%
CI, 3.8 to 14.8;
P=0.001).
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EDV, ESV, and EDD (like EF) improved at the
time of second follow-up, as shown in
Table 2. A shift in the distribution of patients from
greater to lesser severity of heart failure in the immunosuppression
group was found, but this difference was not statistically significant
(P=0.063). The carry-forward
analysis revealed further amplification of the benefit in the
immunosuppression-treated patients at 1 year. In relation to baseline
data, mean EF increased significantly in the immunosuppression group
compared with the placebo group (95% CI, 5.5 to 17.7;
P<0.001). In addition, EDV,
ESV, and EDD improved significantly in the immunosuppression group.
However, there was no difference in NYHA functional class between the
studied groups (P=0.165). The
improvement found in previous follow-up in the immunosuppression group
compared with the placebo group was maintained at 2 years. A
consistent, significant increase in mean EF in the
immunosuppression group was noted (95% CI, 6.9 to 19;
P<0.001;
Figure 2). The remaining secondary efficacy end points were
also significantly different and favored immunosuppression-treated
patients. Immunosuppressive therapy was also associated with long-term
significant improvement in NYHA functional class
(P=0.005;
Table 2).
Clinical Outcomes Based on the
Protocol-Specified Definition of Improvement
The forecasted early and long-term benefits of
immunosuppression among patients with
immunohistologically diagnosed myocarditis are
substantial. On the basis of the protocol-specified definition, 28 of
39 patients (71.8%) in the immunosuppression group versus 9 of 43
patients (20.9%) in the placebo group met the criteria of improvement
(P<0.001) at 3 months. After 6
months, such improvement was found in 30 of 37 patients (81.1%) from
the immunosuppression group compared with 10 of 41 patients (24.4%)
from the placebo (P<0.001).
Similarly, 24 of 35 patients (68.6%) from the immunosuppression group
and 11 of 39 patients (28.2%) from the placebo group improved after 1
year of follow-up (P=0.001).
The clinical improvement by intention-to-treat analysis found
at the previous follow-up was also observed at year 2 in 25 of 35
patients (71.4%) from the immunosuppression group and 12 of 39
patients (30.8%) from the placebo group
(P=0.001). Interestingly, at
the 2-year follow-up among nonrandomized,
immunohistologically negative patients,
protocol-defined improvement was present in 23 of 53 subjects
(43.4%).
Adverse Drug Effects
During immunosuppressive therapy, side effects were
observed in 16 of 41 patients (39%). The increased body weight (>5
kg) due to steroids after 90 days of therapy was present in 14 of
41 patients (34%) in the immunosuppression group. Two of 41 patients
(4.9%) developed hypertension at the time of immunosuppressive
treatment.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Our results have shown, for the first time, that short-term immunosuppressive therapy with steroids and azathioprine may provide long-term benefit in patients with chronic heart failure and immunohistologically proven myocarditis, presented here as an upregulation of HLA on biopsy specimens. Our study was based on the assumption that myocarditis is, at least in part, an immunological disorder and that immunosuppressive treatment will be successful if ongoing inflammation is detectable by immunohistochemistry. It seems that if patients are selected for immunosuppression on the basis of the upregulation and induction of HLA on biopsy specimens, immunosuppressive therapy may significantly improve clinical status. Therefore, we postulate that qualification for this approach should be based on immunohistochemistry instead of histopathological diagnosis or clinical suspicion of myocarditis. These data did not show, however, that immunosuppressive therapy yielded a better survival rate than conventional therapy. This observation is in accord with previous studies on a related subject.15 19 Accordingly, it may be postulated that causes of fatal cardiac events are related, at least in part, to the advance of the disease rather than pathogenesis or treatment alone.
Immunohistochemistry has recently become useful in the detection of ongoing inflammation in the myocardium.11 20 Our previous study demonstrates that de novo induction of HLA may be the most appropriate immunohistological marker of ongoing inflammation in the myocardium.18 It is known that under physiological conditions, endothelial and other interstitial cells constitutively express low levels of HLA21 ; however, cardiac myocytes do not share these characteristics under normal conditions.22 Specimens from patients with histologically active myocarditis demonstrate increased expression and myocyte induction of these molecules.23 It is worth emphasizing that this immunohistological hallmark of the specimens was also found in Chagasic cardiomyopathy, which is postulated as a human model of chronic myocarditis.24
It seems that the immunological mechanisms are independent of clinical presentation of myocarditis and that the chronic inflammatory process has an autoimmunological component, regardless of the trigger mechanism initiating it.25 Because the final targets for immunosuppression are the same, it may be possible that short-term therapy could interrupt the autoimmune response in the myocardium.12 Moreover, the short duration of immunosuppression may also reduce the side effects of such therapy.26 Unlike current results, in the first randomized treatment trial conducted by Parrillo et al,15 there was no observed long-term benefit of steroid therapy in patients with idiopathic dilated cardiomyopathy. This discrepancy of remote outcome is due to study design differences between the trials. In Parrillo et al’s study,15 the entrance criteria were based on clinical status. Moreover, the immunosuppressive regiment consisted of steroids alone. In the present study, the design was based on HLA expression and induction in biopsy as the sole criterion for a patient’s randomization. Furthermore, we used a 2-component immunosuppressive regimen involving steroids and azathioprine. Interestingly, in the light of the present evidence, the final conclusion of Parrillo et al’s study15 that steroids should not be used as a standard therapy for dilated cardiomyopathy is still topical.
Active myocarditis (as based on Dallas criteria) was found in 8% of studied patients. In early reports, the prevalence of myocarditis in biopsies from patients with unexplained congestive heart failure ranged from 4% to 80%.27 These results show that a histopathological diagnosis of myocarditis based on these criteria is difficult because of the focal nature of the inflammatory lesions in the myocardium, which contributes to sampling error.28 Moreover, the pathogenic role of lymphocytes in the myocardium remains unclear because they do not necessarily reflect activated or cytotoxic cells.29 In relation to the facts noted above, the randomized study conducted by Masson at al17 failed to demonstrate the benefit of immunosuppressive therapy in patients with histopathologically proven myocarditis. When we used immunohistological criteria to detect myocarditis, the clinical outcome was different from that found by Masson et al17 but consistent with the results of the previous nonrandomized studies by Maisch et al26 and Kühl and Schultheis,30 which suggested a beneficial effect of immunosuppressive therapy in patients with immunohistologically proven myocarditis.
Although the study was not designed to examine immunohistologically negative patients, it is worth emphasized that 43% of nonrandomized, immunohistologically negative, and conventionally treated patients improved after 2 years compared with 30% of the randomized placebo patients. Such spontaneous improvement has been previously reported in patients with dilated cardiomyopathy and myocarditis.31 It may be hypothesized that in nonrandomized patients there was no true ongoing myocarditis, but only transient autoimmunity, which may respond better to conventional therapy.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Our data demonstrate a significant benefit of 2-component immunosuppression in patients with HLA upregulation on biopsy specimens. Considering the results, we propose restoring immunosuppressive therapy in patients with immunohistologically proven myocarditis. This treatment should be based on immunohistological examination of the biopsy specimens rather than histopathological diagnosis or clinical suspicion of the disease alone. In addition, because immunological markers of inflammation are distributed throughout the myocardium, this approach will likely lead to a lower incidence of false-negative diagnosis and it will significantly decrease the number of postbiopsy complications; hence, fewer specimens will be required.
Study Limitations
The present study may be limited by the exclusion
of patients without increased expression of HLA on biopsy specimens
from randomization. Only patients with HLA upregulation were selected
for randomization. This approach was based on the results of previous
studies that failed to demonstrate effectiveness of immunosuppressive
therapy in clinically diagnosed idiopathic dilated
cardiomyopathy and/or histopathologically verified
myocarditis. However, a few nonrandomized studies demonstrated clinical
benefit of immunosuppressive treatment in patients with
immunohistologically proven myocarditis. Because
steroid therapy is identifiable clinically by the development of
cushingoid features, the assigned treatment was known during the
trial.
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Acknowledgments |
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This study was supported by a grant (0519/PO5/98/15) from the Scientific Research Committee of the Polish Ministry of Health. We are grateful to Zbigniew Kadzio
a, MSc, for
excellent statistical
assistance. Received January 31, 2001; revision received March 28, 2001; accepted April 10, 2001.
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R. Dennert, H. J. Crijns, and S. Heymans Acute viral myocarditis Eur. Heart J., September 1, 2008; 29(17): 2073 - 2082. [Abstract] [Full Text] [PDF]
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I. Kindermann, M. Kindermann, R. Kandolf, K. Klingel, B. Bultmann, T. Muller, A. Lindinger, and M. Bohm Predictors of Outcome in Patients With Suspected Myocarditis Circulation, August 5, 2008; 118(6): 639 - 648. [Abstract] [Full Text] [PDF]
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L. van Heerebeek, N. Hamdani, M. L. Handoko, I. Falcao-Pires, R. J. Musters, K. Kupreishvili, A. J.J. Ijsselmuiden, C. G. Schalkwijk, J. G.F. Bronzwaer, M. Diamant, et al. Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension Circulation, January 1, 2008; 117(1): 43 - 51. [Abstract] [Full Text] [PDF]
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L. T. Cooper, K. L. Baughman, A. M. Feldman, A. Frustaci, M. Jessup, U. Kuhl, G. N. Levine, J. Narula, R. C. Starling, J. Towbin, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: A Scientific Statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology Eur. Heart J., December 2, 2007; 28(24): 3076 - 3093. [Full Text] [PDF]
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P. E. F. Daubeney, A. W. Nugent, P. Chondros, J. B. Carlin, S. D. Colan, M. Cheung, A. M. Davis, C.W. Chow, R. G. Weintraub, and on behalf of the National Australian Childhood Car Clinical Features and Outcomes of Childhood Dilated Cardiomyopathy: Results From a National Population-Based Study Circulation, December 12, 2006; 114(24): 2671 - 2678. [Abstract] [Full Text] [PDF]
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H. N. Skouri, G. W. Dec, M. G. Friedrich, and L. T. Cooper Noninvasive Imaging in Myocarditis J. Am. Coll. Cardiol., November 21, 2006; 48(10): 2085 - 2093. [Abstract] [Full Text] [PDF]
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J. W. Magnani and G. W. Dec Myocarditis: Current Trends in Diagnosis and Treatment Circulation, February 14, 2006; 113(6): 876 - 890. [Full Text] [PDF]
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K. L. Baughman Diagnosis of Myocarditis: Death of Dallas Criteria Circulation, January 31, 2006; 113(4): 593 - 595. [Full Text] [PDF]
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R. R. Marty, S. Dirnhofer, N. Mauermann, S. Schweikert, S. Akira, L. Hunziker, J. M. Penninger, and U. Eriksson MyD88 Signaling Controls Autoimmune Myocarditis Induction Circulation, January 17, 2006; 113(2): 258 - 265. [Abstract] [Full Text] [PDF]
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E. T. Jaeggi, J.-C. Fouron, E. D. Silverman, G. Ryan, J. Smallhorn, and L. K. Hornberger Transplacental Fetal Treatment Improves the Outcome of Prenatally Diagnosed Complete Atrioventricular Block Without Structural Heart Disease Circulation, September 21, 2004; 110(12): 1542 - 1548. [Abstract] [Full Text] [PDF]
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J. W Mason Myocarditis and dilated cardiomyopathy: An inflammatory link Cardiovasc Res, October 15, 2003; 60(1): 5 - 10. [Abstract] [Full Text] [PDF]
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M. Noutsias, M. Pauschinger, H.-P. Schultheiss, and U. Kuhl Cytotoxic perforin+ and TIA-1+ infiltrates are associated with cell adhesion molecule expression in dilated cardiomyopathy Eur J Heart Fail, August 1, 2003; 5(4): 469 - 479. [Abstract] [Full Text] [PDF]
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A. Frustaci, C. Chimenti, F. Calabrese, M. Pieroni, G. Thiene, and A. Maseri Immunosuppressive Therapy for Active Lymphocytic Myocarditis: Virological and Immunologic Profile of Responders Versus Nonresponders Circulation, February 18, 2003; 107(6): 857 - 863. [Abstract] [Full Text] [PDF]
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M. Noutsias, M. Pauschinger, U. Kuhl, and H.-P. Schultheiss Immunosuppressive treatment in familial dilated cardiomyopathy with biopsy-proven intramyocardial inflammation? J. Am. Coll. Cardiol., January 1, 2003; 41(1): 169 - 169. [Full Text] [PDF]
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S.B. Felix, A. Staudt, and G. Baumann Immunoadsorption as a new therapeutic principle for treatment of dilated cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I63 - I68. [Abstract] [PDF]
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A. Frustaci, M. Pieroni, and C. Chimenti Immunosuppressive therapy in inflammatory cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I69 - I72. [Abstract] [PDF]
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U. Kuhl, M. Pauschinger, M. Noutsias, J.-F. Kapp, and H.-P. Schultheiss Diagnosis and treatment of patients with virus induced inflammatory cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I73 - I80. [Abstract] [PDF]
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S. B. Felix, A. Staudt, M. Landsberger, Y. Grosse, V. Stangl, T. Spielhagen, G. Wallukat, K. D. Wernecke, G. Baumann, and K. Stangl Removal of cardiodepressant antibodies in dilated cardiomyopathy by immunoadsorption J. Am. Coll. Cardiol., February 20, 2002; 39(4): 646 - 652. [Abstract] [Full Text] [PDF]
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J. E. Parrillo Inflammatory Cardiomyopathy (Myocarditis) : Which Patients Should Be Treated With Anti-Inflammatory Therapy? Circulation, July 3, 2001; 104(1): 4 - 6. [Full Text] [PDF]
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