Skip Navigation


European Heart Journal Advance Access originally published online on June 13, 2008
European Heart Journal 2008 29(16):1949-1955; doi:10.1093/eurheartj/ehn268
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/16/1949    most recent
ehn268v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Leuschner, F.
Right arrow Articles by Kaya, Z.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leuschner, F.
Right arrow Articles by Kaya, Z.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction

Florian Leuschner1,{dagger}, Jin Li1,{dagger}, Stefan Göser1, Lars Reinhardt1, Renate Öttl1, Peter Bride1, Jörg Zehelein1, Gabriele Pfitzer2, Andrew Remppis1, Evangelos Giannitsis1, Hugo A. Katus1 and Ziya Kaya1,*

1 Department of Internal Medicine III, Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
2 Institute of Vegetative Physiology, University of Cologne, 50931 Köln, Germany

Received 30 December 2007; revised 25 April 2008; accepted 29 May 2008; online publish-ahead-of-print 13 June 2008.

* Corresponding author. Tel: +49 62215639617, Fax: +49 6221565017, Email: ziya.kaya{at}med.uni-heidelberg.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: Application of antibodies against cardiac troponin I (cTnI-Ab) can induce dilation and dysfunction of the heart in mice. Recently, we demonstrated that immunization with cTnI induces inflammation and fibrosis in myocardium of mice. Others have shown that auto-antibodies to cTnI are present in patients with acute coronary syndrome, but little is known about the clinical relevance of detected cTnI-Ab.

Methods and results: First, anti-cTnI and anti-cTnT antibody titres were measured in sera from 272 patients with dilated- (DCM) and 185 with ischaemic- (ICM) cardiomyopathy. Secondly, 108 patients with acute myocardial infarction (AMI) were included for a follow-up study. Heart characteristics were determined by magnetic resonance imaging 4 days and 6–9 months after AMI. Altogether in 7.0% of patients with DCM and in 9.2% with ICM, an anti-cTnI IgG antibody titre ≥1:160 was measured. In contrast, only in 1.7% of patients with DCM and in 0.5% with ICM, an anti-cTnT IgG antibody titre ≥1:160 was detected. Ten out of 108 patients included in the follow-up study were tested positive for cTnI-Ab with IgG Ab titres ≥1:160. TnI-Ab negative patients showed a significant increase in left ventricular ejection fraction (LVEF) and stroke volume 6–9 months after AMI. In contrast, there was no significant increase in LVEF and stroke volume in TnI-Ab positive patients.

Conclusion: We demonstrate for the first time that the prevalence of cTnI-Abs in patients with AMI has an impact on the improvement of the LVEF over a study period of 6–9 months.

Key Words: Cardiac troponin • Autoantibody • Cardiomyopathy • Myocardial infarction

{dagger} Equally contributed. Back


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
After myocardial infarction (MI), the heart undergoes sophisticated repairing processes that involve cardiomyocytes of the ischaemic region, the surrounding areas, as well as changes in the extracellular matrix. As reviewed by Liao and Cheng,1 previous research strongly emphasizes the implication of the immune system in this post-MI phase. Especially in patients with dilated cardiomyopathy (DCM), a variety of antibodies were detected being directed against cardiac proteins such as β1-adrenergic receptor, Na+/K+-ATPase, myosin, actin, and the troponins.2–12 Positive antibody titre correlated with a higher morbidity and a worse outcome compared to patients without anti-heart antibodies. Moreover, experimental models demonstrated that adoptive T-cell transfer of splenocytes from post-MI-mice into healthy syngeneic rodents led to severe myocardial inflammation and subsequent heart dysfunction, which provides direct evidence of a cell-mediated immune response.13 Altogether, the findings suggest the involvement of both humoral and cellular immune system in the pathophysiology of ventricular remodelling after MI.

Cardiac troponins have become the gold standard biomarkers for the acute coronary syndrome, as they indicate myocardial cell damage with high sensitivity and specificity. After a myocardial infarction, they are released into the bloodstream, where they are normally absent. Once they have entered the systemic circulation, they present previously concealed auto-antigens that carry the potential to trigger the host's immune system thus initiating an autoimmune response with production of cTnI antibodies. Okazaki et al.14 demonstrated with PD1-deficient mice that auto-antibodies against cTnI induce the development of cardiac dysfunction and dilation by stimulating the Ca2+ influx in cardiomyocytes. Others have shown that auto-antibodies to cTnI are present in patients with acute coronary syndrome and that these antibodies may interfere with diagnostic assays leading to unpredictable results.15 These findings indicate that induction of an autoimmune response to cTnI is not a rare event in patients but is rather underappreciated. Recently, we showed that an autoimmune response to murine cardiac troponin I (mcTnI) induces severe inflammation in the myocardium followed by fibrosis and heart failure with increased mortality in mice. Furthermore, we demonstrated that mice immunized with mcTnI prior to LAD ligation showed greater infarct size, more fibrosis, higher inflammation scores, and reduced fractional shortening.16

In our present study, we first screened patients with DCM or ICM for the presence of anti-cTnI and anti-cTnT antibodies. Then, we pursued their potential effect on the cardiac function after acute myocardial infarction (AMI). For this purpose, we followed-up 108 patients with acute MI regarding their heart function and the presence of anti-cTn antibody titres. Evolution of cardiac remodelling was determined by magnetic resonance imaging (MRI) that was performed after a median of 4 days after admission and after 6–9 months. Finally, we investigated whether auto-antibodies against troponin I can be found in healthy subjects and athletes with general trauma to the skeletal muscular system. We therefore, measured anti-cTnI antibodies in sera from athletes running a 216 km ultra-endurance marathon in Death Valley.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
Study population
Patients with cardiomyopathies
To get a general impression of antibodies against troponin I and T in patients with cardiomyopathies, we performed a retrospective analysis measuring antibody-titres in sera from a total of 457 patients, among which 272 had a DCM, while 185 had an ischaemic cardiomyopathy (ICM). Inclusion criteria for ICM-patients were previously documented MI and coronary artery disease with a left ventricular ejection fraction (LVEF) of less than 40%. For DCM-patients, inclusion criteria were exclusion of coronary artery disease and an LVEF under 40%. Blood was collected in our cardiac catheter laboratory. All patients gave informed consent.

Patients with acute myocardial infarction and follow-up
Another 108 patients with AMI were separately considered in our observational follow-up study. Their inclusion criteria were as follows: all patients presented with AMI to the chest pain unit of the University Hospital of Heidelberg, Germany. Patients were included from October 2005 until August 2006. Through a 12-lead ECG and measuring cardiac troponin T (cTnT) in serum, they were either identified as ST-elevation myocardial infarction (STEMI) or as non-ST-elevation myocardial infarction (NSTEMI). All patients underwent percutaneous transluminal coronary angiography and were treated according to the ACC/AHA guidelines. Heart characteristics were determined by MRI on day 3–4 after MI. After 6–9 months MRI was repeated. Furthermore, laboratory parameters were evaluated. Patients with autoimmune diseases, active infections, cancer, or heart failure of other known origins than MI were excluded. All patients received stable oral medication according to the ACC/AHA guidelines from 200417 (acetylsalicylic acid, clopidogrel, renin–angiotensin–aldosterone-system-blocker, beta blocker, statin). The local ethic commissions approved the study protocol and written informed consent was obtained from all patients.

Healthy subjects and athletes with general trauma to the skeletal muscular system
Sera from 10 healthy male athletes [median (25th/75th percentile)] aged 52 (43/57) years, height 177 (170/182) cm, weight 75 (71/78) kg, and body mass index 24 (23/25) kg/m2 who participated in the Badwater ultra-marathon 2004 were analysed and screened for the presence of antibodies against troponin I and T. Runners were initially included for a cardiospecifity study of the third generation cTnT assay.18 Ethical approval was obtained from the ethics committee, Münster, Germany. Written informed consent from each athlete prior to study participation was obtained. The Badwater marathon is a continuous 216 km (134 miles) race, which takes place in July under extreme heat in Death Valley, CA, USA. The start line is at Badwater, Death Valley, which marks the lowest elevation in the Western hemisphere at 282 feet (85.5 m) below sea level. The race finishes at the Mt Whitney Portals at 8.360 feet (2.533 m).

Each of the 10 experienced athletes had previously completed 43.4 marathon and 20.4 ultra-marathon races. No athlete had a history of cardiovascular disease, hypertension, or any significant comorbidity. None of the subjects was taking cardiovascular drugs. One athlete suffers from type I diabetes since childhood with continuously low HbA1c values <6%. Stationary laboratories fully equipped, ensuring proper pre-analytical conditions like specimen centrifugation and specimens freezing at –80°C (dry-ice) were installed at Stovepipe Wells (Lab1) and Lonepine (Lab2). Blood was collected at the start (E0), after the first half-marathon distance (E1), after each full marathon distance (E2–E6), and at the end (E7). Blood samples (whole blood, EDTA-blood) were kept on crushed ice in the supporters’ car until the shuttle service took over the specimens transferring them to the stationary laboratories for pre-analytical preparation. One EDTA-blood sample was transferred to a laboratory in Las Vegas on a daily basis on crushed ice for blood-count testing. The samples were transferred by WorldCourier® that documented an uninterrupted cold chain to the Laboratory in Heidelberg, Germany. No sample showed any sign of haemolysis.

During the run, concentrations of CK, CK-MBact, and CK-MBmass significantly increased, while cTnT-concentration remained below detectable levels in all runners.18

Enzyme-linked immunoabsorbent assay (ELISA)
Peripheral venous blood samples were collected from all patients. Ninety-six well plates were coated with anti-cTnI or anti-cTnT diluted in coating buffer (0.1 M NaHCO3/34 mM Na2CO3, pH 9.5) and then incubated over night at 4°C. All washing steps were performed with 1x PBS/0.05% Tween 20 three times each. One percent Gelatine (Cold Water Fish, Sigma)/1xPBS was used for blocking. After 2 h incubation at 37°C, half of the plate was coated with human cTnI or cTnT for another 2 h at room temperature (RT) while the other half served as control, thus, only coated with 1x PBS/1%BSA/0.1% Tween 20. The dilution series of the serum samples were as follows: 1:40, 1:80, 1:160, and 1:320. For 1 h 30 min, the plates were incubated at RT. HRP anti-human IgG or anti-human IgM (diluted 1:7500 with 1x PBS/1% BSA/0.1% Tween 20, 1 h incubation at RT) was used as detection-antibody. Blue Star HRP-Substrate from Diarect was applied for 45 min at RT. The reaction was stopped with 0.3 M H2SO4. Finally, the absorbance was measured at 450 nm. We used a hybrid antibody construct (Fc-fragment = human IgG + Fab-fragment = mouse antihuman cTnI or cTnT; provided by Roche Diagnostics, Mannheim, Germany) as a positive control. Sera from healthy persons, mouse serum, and buffer alone served as negative controls. To calculate the cTnI titres, the optical densities on both halves of the plate of each sample and dilution were subtracted. Total IgG antibody titres were measured in all patients. Additionally, we measured total IgM antibody titres in the follow-up study patients. Total antibody endpoint titres for each sample were calculated as the highest positive dilution of antibody.

Cardiac magnetic resonance imaging
MRI examinations were performed with a 1.5 Tesla whole-body MRI system (Philips Medical Systems, 1.5 Tesla). Functional and morphological cardiac assessment was adequately executed in all 108 MI patients. Duration of MRI scan was approximately 30–60 min. Patients were examined for several parameters such as the LVEF, the end-systolic volume, the end-diastolic volume, and the stroke volume. Infarct size was calculated as previously described.19 All data were provided by independent examiners, on hospital admission and 6–9 months after MI.

Statistical analysis
For the DCM/ICM study population, the McNemar test was used to evaluate the relationship between auto-antibodies against cTnI and cTnT, separately for each group.

As for the patients undergoing MRI investigations, they were compared with respect to their initial demographic data including cardiovascular risk factors and oral medication. The two-sided Mann–Whitney U test was adopted to compare the continuous parameters, while the two-sided {chi}2 test was applied for the categorical data. The main criterion for the MRI examination was the LVEF. For this parameter, a confirmatory comparison controlling the {alpha}-error was carried out to compare the difference of the MRI data on day 3–4 and 6–9 months later between the titre positive and negative groups. All other MRI data were exploratory analysed and the resulting P-values cannot be interpreted in a confirmatory sense. To compare the difference in the MRI parameters, a univariate analysis of covariance was applied considering the value on admission as covariate in order to account for the slight imbalance in the distribution of the parameters between the groups in the baseline MRI. Due to the small sample size of the titre positive group, we dispensed with a multivariable analysis of covariance including further parameter. A P-value < 0.05 was considered significant though only the analysis of the LVEF can be interpreted in a confirmatory sense. All calculations were carried out with SPSS, version 15.0. Analysis was done blinded.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
Cardiac troponin I- and cardiac troponin T-auto-antibodies in dilated cardiomyopathy and ischaemic cardiomyopathy patients
Out of 457 patients, 27.9% DCM-patients (n = 272) and 27.6% ICM-patients (n = 185) showed a positive total IgG antibody titre against cTnI ≥ 1:40. A total IgG titre ≥ 1:80 was present in 14.3% of the DCM-patients and in 17.3% of the ICM-patients and a titre ≥1:160 was present in 7.0% of the DCM-patients and in 9.2% of the ICM-patients. In contrast, only 5.2% of DCM-patients and 1.6% of ICM-patients had cTnT total IgG antibodies with a titre ≥ 1:40, 1.8% of DCM-patients and 0.5% of ICM-patients had a titre ≥ 1:80, and 1.7% of DCM-patients and 0.5% of ICM-patients had a titre ≥1:160 (Table 1). Further subdivision according to gender presented the following pattern: overall, 28.5% of the anti-cTnI antibody titre ≥ 1:40 were male, 26.3% were female [no significance (NS)]. The age distribution revealed a positive titre ≥ 1:40 in 35.1% of the patients over 65 years and 35.4% of those younger than 65 (NS, data not shown).


View this table:
[in this window]
[in a new window]

  		Table 1 Cardiac troponin I- and cardiac troponin T-auto-antibodies in dilated cardiomyopathy and ischaemic cardiomyopathy patients

 
Baseline characteristics of patients with acute myocardial infarction and follow-up
All 108 MI patients (mean age 60.1 ± 11.3 years, 82% males) were classified into two groups regarding their antibody titres: 98 patients (mean age 59.9 ± 11.6 years, 82% males) were found negative for cTnI antibodies, while in 10 patients (mean age 62.9 ± 8.0 years, 80% males) total IgG antibody titres ≥ 1:160 were detected. Their heart rates (mean HR 72.1 ± 13.2 min–1) were considered as well as their blood pressures at hospital presentation (mean RR 131.2/80.1 ± 19.0/14.2 mmHg). The infarct size measured by MRI was 17.3 g ± 15.3 in average. cTnT and NTproBNP levels 72–96 h after the acute event were comparable for both groups (1.7 ± 1.4 vs. 1.5 ± 0.8 µg/L; P = 0.96 and 1076.2 ± 989.0 vs. 2515.6 ± 4515.3 ng/L; P = 0.61). There were no significant differences in baseline characteristics between patients with positive and negative cTnI titres (Table 2). Two patients were not treated with clopidogrel due to severe bleeding complications.


View this table:
[in this window]
[in a new window]

  		Table 2 Baseline data of patients, risk factors, and medication at discharge of both antibodies against cardiac troponin I negative and positive patients

 
Presence of cardiac troponin antibodies and left ventricular ejection fraction
For assessment of development of cardiac function, each patient underwent examination through MRI on day 4 after admission and 6–9 months thereafter. Blood samples from all patients were analysed on both time-points. Patients that were cTnI-Ab-positive (titre ≥ 1:160) at the time of acute MI remained positive, three of them showed even higher optical densities. Only one patient had total IgM antibodies against cTnI with a titre ≥ 1:160 and one patient had total IgG antibodies against cTnT with a titre ≥1:160.

Patients with a negative total IgG antibody titre against cTnI revealed an increase in LVEF from 54.6 ± 9.6 to 59.7 ± 9.2% (Table 3 and Figure 1) in contrast to the group of patients with total IgG antibody titres ≥1:160 against cTnI with no comparable improvement in LVEF (from 57.4 ± 10.9 to 56.0 ± 11.6%, P = 0.031) (Table 3 and Figure 2).


View this table:
[in this window]
[in a new window]

  		Table 3 MRI-data on admission (3–4 days post-MI) and on follow-up (6–9 months post-MI)

 

Figure 1
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Dot and line diagram: LVEF of Tnl-Ab negative patients.

 

Figure 2
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Dot and line diagram: LVEF of Tnl-Ab positive patients. n.s., not significant.

 
Measurement of antibody titres in healthy subjects and athletes with general trauma to the skeletal muscular system
In none of the 10 athletes running, the ultra marathon antibodies against troponin I or T with a titre ≥ 1:160 were detectable. One runner developed exercise-induced rhabdomyolysis with spontaneous recovery with a peak CK of 27.951 U/L.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
After a myocardial infarction, cardiac troponins are released into the systemic circulation. As their localization is thought to be strictly intracellular, the immune system of the MI patient is then being exposed to previously unknown antigens, whereupon the immune system is triggered to produce antibodies against cardiac troponins. Earlier studies have indeed described anti-cTnI auto-antibodies in patients, while to our knowledge no studies exist investigating the presence of antibodies against cTnT in patients. Furthermore, the clinical impact of existing anti-troponin antibodies has never been explored so far.2 To answer these questions, we first screened over 400 serum samples collected from DCM and ICM patients for the presence of cTnI- and cTnT-auto-antibodies. The results provided evidence for the presence of anti-cTnI as well as for anti-cTnT antibodies, even though of much lesser extent. The characterization of their titre pattern revealed no differences regarding gender or age (cut-off 65 years) of the patients.

Recently, we showed that induction of an immune response to cTnI leads to the development of severe myocardial inflammation in mice, in contrast to cTnT, which induces little or no effect in myocardium.16 Okazaki et al.14 demonstrated with PD1-deficient mice that auto-antibodies against cTnI induce the development of cardiac dysfunction and dilatation by stimulating the Ca2+ influx in cardiomyocytes. Therefore, we further investigated the clinical relevance of cTnI auto-antibodies in humans with ischaemic heart disease. We followed up MI-patients regarding the presence of cTnI antibody titres and their heart function on admission as well as 6–9 months later. Out of 108 patients, 98 were considered as titre negative (total IgG antibody titre <1:160), whereas 10 had a titre ≥1:160. Both groups showed comparable demographic data and cardiovascular risk factor constellation. Patients with antibodies against troponin I remained positive on the follow-up visit, three of them even showing higher optical densities. In contrast, none of the initially negative patients developed auto-antibodies against troponin during the follow-up phase. This could be due to the shortness of our observation time and a general susceptibility towards an autoimmune reaction. We believe that those patients presenting with a positive titre at the time of the acute infarction had experienced ‘silent’ release of troponins before the actual AMI and thus had developed the antibodies prior to the event. This hypothesis is supported by a report from Zethelius et al.,20 who detected cTnI in men free from coronary heart disease, which was shown to predict death and first CAD event. Our data collected from MRI revealed a significant improvement in LVEF through time to the anti-cTnI positive group (P = 0.031). These antibodies as of a titre ≥1:160 seem to have a restraining effect on the recovery of the heart after myocardial injury, as the patients with a lower titre or no titre showed amelioration in heart function after 6–9 months.

One might assume that smaller lesions in skeletal muscle can prompt an immunization or cross-reactivity. We, therefore, analysed blood samples from athletes running a 216 km ultra-endurance marathon. These well-trained athletes all had great experience and a history of marathons run before the time-point of the analysis. It is therefore very likely that their immune system had already been confronted with the release of cardiac proteins (and skeletal troponins) before. However, none of them showed elevated titres for antibodies against cardiac troponin I or T. Also, the documented rhabdomyolysis in one of the runners did not induce cTnI- or cTnT-antibodies.

These findings may open new opportunities for therapeutic approaches. Comparable to previous studies on patients with DCM in which cardiac haemodynamics improved after immunoadsorption, the removal of anti-cTnI antibodies in patients with a titre ≥ 1:160 may enhance their outcome as well.21,22 Likewise, the auto-antibodies represent possible therapeutic targets to be withdrawn from circulation, with the intention to prevent further inhibiting effects on the repairing process of the myocardium. In contrast, earlier trials applying immunosuppressants such as glucocorticoids and biologicals in patients after MI failed with dissatisfying results.23–25 Despite multiple attempts to characterize the antibodies responsible for the cardiodepressive effect in DCM-patients, no definite actor could be isolated so far.26

The present follow-up study discloses several limitations. Our study is limited by its relatively small number of anti-cTnI positive patients. We used a cut-off of 1:160 for the anti-cTnI antibody (total IgG) titres and classified the patients accordingly as cTnI-antibody negative or positive. Therefore, only 10 persons were found to be anti-cTnI antibody positive. This group of patients showed no improvement of their heart function. Further research is required to clarify the role of the humoral immune system in the post-MI phase, as data on the potential effect of cTnT auto-antibodies or IgM subclasses on the myocardial function are lacking. Moreover, studies with a larger number of patients and with a longer follow-up are needed for more conclusive data towards the patient's prognosis in relation to their antibody titres.

In conclusion, the present study provides for the first time evidence of anti-cTnT antibodies in a small subgroup of patients with dilated and ICM. Furthermore, our findings suggest that auto-antibodies against cTnI in patients with myocardial infarction may play a role in the ventricular remodelling process of the myocardium after infarction.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
This work was supported by the Ernst und Berta Grimmke Stiftung and by the Deutsche Forschungsgemeinschaft (KA 1797/3-1) to Z.K. and in part by SFB 612 to G.P.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
The authors thank Özay Kaya, Theresa Tretter, and Simone Höger for critically reading the manuscript, Mirja Neizel for helping in analysing the MRI data, Maria Pritsch for statistical support and Heinz J. Roth for providing sera from healthy male athletes.

Conflict of interest: H.A.K. has developed the troponin T assay and holds a patent on this assay jointly with Roche Diagnostics. H.A.K. and Z.K. have applied for the patent entitled ‘measuring troponin antibodies to assess cardiovascular risk’ jointly with Roche Diagnostics. There is nothing else to declare.


   Footnotes
 
{dagger} Equally contributed. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

  1. Liao YH, Cheng X. Autoimmunity in myocardial infarction. Int J Cardiol (2006) 112:21–26.[CrossRef][Web of Science][Medline]
  2. Shmilovich H, Danon A, Binah O, Roth A, Chen G, Wexler D, Keren G, George J. Autoantibodies to cardiac troponin I in patients with idiopathic dilated and ischemic cardiomyopathy. Int J Cardiol (2007) 117:198–203.[CrossRef][Web of Science][Medline]
  3. Caforio AL, Daliento L, Angelini A, Bottaro S, Vinci A, Dequal G, Tona F, Iliceto S, Thiene G, McKenna WJ. Autoimmune myocarditis and dilated cardiomyopathy: focus on cardiac autoantibodies. Lupus (2005) 14:652–655.[Abstract/Free Full Text]
  4. Wallukat G, Morwinski M, Kowal K, Forster A, Boewer V, Wollenberger A. Autoantibodies against the beta-adrenergic receptor in human myocarditis and dilated cardiomyopathy: beta-adrenergic agonism without desensitization. Eur Heart J (1991) 12(Suppl. D):178–181.[Abstract/Free Full Text]
  5. Limas CJ, Limas C. Beta-adrenoceptor antibodies and genetics in dilated cardiomyopathy—an overview and review. Eur Heart J (1991) 12(Suppl. D):175–177.[Abstract/Free Full Text]
  6. Magnusson Y, Wallukat G, Waagstein F, Hjalmarson A, Hoebeke J. Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect. Circulation (1994) 89:2760–2767.[Abstract/Free Full Text]
  7. Baba A, Yoshikawa T, Ogawa S. Autoantibodies produced against sarcolemmal Na-K-ATPase: possible upstream targets of arrhythmias and sudden death in patients with dilated cardiomyopathy. J Am Coll Cardiol (2002) 40:1153–1159.[Abstract/Free Full Text]
  8. De S I, Vandekerckhove J, Robbrecht J, Algoed L, De Buyzere M, De Langhe J, De Schrijver G, Clement D. Post-cardiac injury syndrome and an increased humoral immune response against the major contractile proteins (actin and myosin). Am J Cardiol (1985) 56:631–633.[CrossRef][Web of Science][Medline]
  9. De S I, de Buyzere ML, Delanghe JR, Clement DL, Wieme RJ. Anti-myosin humoral immune response following cardiac injury. Autoimmunity (1989) 4:51–58.[Medline]
  10. 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]
  11. Goldman JH, Keeling PJ, Warraich RS, Baig MK, Redwood SR, Dalla LL, Sanderson JE, Caforio AL, McKenna WJ. Autoimmunity to alpha myosin in a subset of patients with idiopathic dilated cardiomyopathy. Br Heart J (1995) 74:598–603.[Abstract/Free Full Text]
  12. Eriksson S, Hellman J, Pettersson K. Autoantibodies against cardiac troponins. N Engl J Med (2005) 352:98–100.[Free Full Text]
  13. Maisel A, Cesario D, Baird S, Rehman J, Haghighi P, Carter S. Experimental autoimmune myocarditis produced by adoptive transfer of splenocytes after myocardial infarction. Circ Res (1998) 82:458–463.[Abstract/Free Full Text]
  14. Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, Ishida M, Hiai H, Matsumori A, Minato N, Honjo T. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med (2003) 9:1477–1483.[CrossRef][Web of Science][Medline]
  15. Eriksson S, Halenius H, Pulkki K, Hellman J, Pettersson K. Negative interference in cardiac troponin I immunoassays by circulating troponin autoantibodies. Clin Chem (2005) 51:839–847.[Abstract/Free Full Text]
  16. Goser S, Andrassy M, Buss SJ, Leuschner F, Volz CH, Ottl R, Zittrich S, Blaudeck N, Hardt SE, Pfitzer G, Rose NR, Katus HA, Kaya Z. Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardium. Circulation (2006) 114:1693–1702.[Abstract/Free Full Text]
  17. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr, Alpert JS, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. (2004) 110:e82–e292.
  18. Roth HJ, Leithauser RM, Doppelmayr H, Doppelmayr M, Finkernagel H, von Duvillard SP, Korff S, Katus HA, Giannitsis E, Beneke R. Cardiospecificity of the 3rd generation cardiac troponin T assay during and after a 216 km ultra-endurance marathon run in Death Valley. Clin Res Cardiol (2007) 96:359–364.[CrossRef][Web of Science][Medline]
  19. Giannitsis E, Steen H, Kurz K, Ivandic B, Simon AC, Futterer S, Schild C, Isfort P, Jaffe AS, Katus HA. Cardiac magnetic resonance imaging study for quantification of infarct size comparing directly serial versus single time-point measurements of cardiac troponin T. J Am Coll Cardiol (2008) 51:307–314.[Abstract/Free Full Text]
  20. Zethelius B, Johnston N, Venge P. Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study. Circulation (2006) 113:1071–1078.[Abstract/Free Full Text]
  21. Felix SB, Staudt A, Dorffel WV, Stangl V, Merkel K, Pohl M, Docke WD, Morgera S, Neumayer HH, Wernecke KD, Wallukat G, Stangl K, Baumann G. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study. J Am Coll Cardiol (2000) 35:1590–1598.[Abstract/Free Full Text]
  22. Dorffel WV, Felix SB, Wallukat G, Brehme S, Bestvater K, Hofmann T, Kleber FX, Baumann G, Reinke P. Short-term hemodynamic effects of immunoadsorption in dilated cardiomyopathy. Circulation (1997) 95:1994–1997.[Abstract/Free Full Text]
  23. Roberts R, DeMello V, Sobel BE. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation (1976) 53:I204–I206.[Medline]
  24. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation (2004) 109:1594–1602.[Abstract/Free Full Text]
  25. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation (2003) 107:3133–3140.[Abstract/Free Full Text]
  26. Wallukat G, Reinke P, Dorffel WV, Luther HP, Bestvater K, Felix SB, Baumann G. Removal of autoantibodies in dilated cardiomyopathy by immunoadsorption. Int J Cardiol (1996) 54:191–195.[CrossRef][Web of Science][Medline]
    The above article uses a new reference style being piloted by the EHJ that shall soon be used for all articles.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Clin. Chem.Home page
M. Adamczyk, R. J. Brashear, and P. G. Mattingly
Prevalence of Autoantibodies to Cardiac Troponin T in Healthy Blood Donors
Clin. Chem., August 1, 2009; 55(8): 1592 - 1593.
[Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
L. Petaja, M. Salmenpera, K. Pulkki, and V. Pettila
Biochemical Injury Markers and Mortality After Coronary Artery Bypass Grafting: A Systematic Review.
Ann. Thorac. Surg., June 1, 2009; 87(6): 1981 - 1992.e3.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
Z. Kaya, S. Goser, S. J. Buss, F. Leuschner, R. Ottl, J. Li, M. Volkers, S. Zittrich, G. Pfitzer, N. R. Rose, et al.
Identification of Cardiac Troponin I Sequence Motifs Leading to Heart Failure by Induction of Myocardial Inflammation and Fibrosis
Circulation, November 11, 2008; 118(20): 2063 - 2072.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/16/1949    most recent
ehn268v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Leuschner, F.
Right arrow Articles by Kaya, Z.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leuschner, F.
Right arrow Articles by Kaya, Z.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?