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The TIMIC study

Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy

Currently there is no consensus on the treatment of inflammatory cardiomyopathy with immunosuppression and the strategies used are those adopted for the management of heart failure. The TIMIC study was initiated to evaluate the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy.
Myocardial Disease

The TIMIC study (1) as a randomized, double-blind, placebo controlled trial included 85 patients with myocarditis and chronic (>6 month) heart failure unresponsive to conventional therapy. All patients have had an endomyocardial biopsy with the presence of > 14 infiltrating leucocytes/mm2 and/or the presence of more than 2 CD3-positive lymphocytes per high power field (hpf). The presence of the genome of cardiotropic viruses was excluded by polymerase chain reaction with primer pairs specific for the 10 most important cardiotropic viruses (adenovirus, Epstein Barr virus, Human herpes virus 6, Parvovirus B 19, Herpes simplex virus 1-2, Cytomegalovirus, enterovirus, influenza A and B viruses, Hepatitis C virus).
Patients received either prednisone 1mg/kg body weight (BW) per day for 4 weeks followed by 0.33 mg/kg BW for 5 months and azathioprine 2mg/kg BW for 6 month (n=42) or placebo (n=42). All patients were on optimal continuous medication with conventional heart failure therapy including digitalis, diuretics, ACE inhibitors and carvedilol 8 weeks prior and during the study.
Primary outcome was the 6 month improvement in left ventricular function, based on the increase of left ventricular ejection fraction assessed by echocardiography. Secondary objectives were changes NYHA functional class and survival differences (cardiac death or heart transplantation.

88% of patients in the treatment group showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left ventricular dimensions and volume compared with baseline. The remaining 5 five patients maintained a stable clinical picture and cardiac function parameters. Even patients with severe advanced disease (LVEDD up to 90mm and LVEF <20%) significantly improved. The percentage of patients who improved by at least 1 NYHA class at 6 month was 49% in the treatment group and none in the placebo group.

None of the patients without specific treatment (placebo) showed improvement of ejection fraction, that significantly worsened compared with baseline in 83% of patients. Seven patients remained stationary. Specifically, after 1 month of treatment, placebo group exhibited in 38% a mild improvement of ejection fraction, that was maintained up to 3 month, but then declined to baseline or lower values.
No major adverse events were registered as a result of immunosuppressive therapy. Minor adverse reactions as increased body weight, glucose blood level elevation, and fluid retension requiring diet, glucoactive drugs, insuline administration, and diuretic dose adjustment were reported in only six patients on immunosuppression.

Control immunohistology at 1 and 6 month showed, that the 38 patients under immunosuppression, who improved, had healed myocarditis with disappearance of inflammatory infiltrates associated with interstitial and focal replacement of fibrosis. In the placebo group findings in endomyocardial biopsies were not dissimilar from baseline, showing persistence of myocarditis as well as expansion of interstitial and replacement fibrosis.
Results of this trial confirmed the positive impact of immunosuppression on recovery of LV function in a high rate of patients with no case of death or cardiac transplantation during treatment and in the following 6 month. Remarkably a striking improvement occurred even in patients with extreme LV dilatation and dysfunction and it was accompanied at histological examination by the disappearance of inflammatory infiltrates with progression of the disease from an active towards a healed myocarditis.
In conclusion, immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy appears as an effective and safe option in addition to supportive treatment for recovery of cardiac failure.


There is reasonable clinical and experimental evidence, that DCM may occur as late stage of cardiac infection and inflammation in a subgroup of patients. Heterogeneity of symptoms, with subclinical or asymptomatic forms, could be the reason, why prevalence of myocarditis and the link to DCM may be underestimated. This large spectrum of clinical forms depends on several factors such as genetic determinants of the infective agent, the genetics, age and gender of the host, and the host immunocompetence. With the development of various new diagnostic modalities, early and definite diagnosis of dilated inflammatory or infectious cardiomyopathy depends, first, on the detection of inflammatory infiltrates in the endomyocardial biopsies according the WHO/ISFC and the Dallas criteria using immunohistochemistry.

Second, molecular techniques such as polymerase chain reaction (PCR), in situ hybridization, gene sequencing and real-time PCR, often applied on the same endomyocardial specimen, are essential for the rapid, specific and sensitive identification of the infective agents.
In addition, the correct application of these methods may allow us to get information on epidemiology, risk stratification in a given patient and a more appropriate medical treatment (2). Because of the overlap of pathophysiological stages in DCM, design of the appropriate therapy is important. It requires the immunohistochemical and molecular biological investigation of endomyocardial biopsies in parallel. 

Therapy for the first virally or bacterially induced stage needs an effective antiviral or antibacterial treatment, especially as viral infection represents an independent unfavourable prognostic factor in patients. Therapy for the second inflammatory stage is an anti-inflammatory therapy, that on the other hand may be harmful, if virus persists in the myocardium (3).

When planning their study, Frustaci et al. have taken care on the different pathophysiological stages of the disease and have used all of the appropriate diagnostic tools that should be used to differentiate the patients.
For this, the TIMIC trial advances our understanding of the role of inflammation in chronic dilated cardiomyopathy. First, their results provide convincing clinical data showing that persisting inflammation causes myocardial dysfunction in their select population.  In addition to this, Kindermann et al. have recently shown, that detection of inflammatory infiltrates in endomyocardial biopsies by immunohistochemistry predict a poor outcome with regard to left ventricular function (4). Persistence of cardiotropic viruses was tested negative by polymerase chain reaction in all of those patients.

Secondly, their use of cell-specific immunocytochemistry to define myocarditis identifies a subset of patients with chronic dilated cardiomyopathy, that respond to immunosuppression. Indirectly, by demonstrating robust improvement in patients without viral genome in the heart, their results support the concept that persistent viral infection is important in the pathogenesis of a different subset of patients with chronic cardiomyopathy (5).
Nevertheless, the clinical endpoints need to be evaluated prospectively because a short-term increase on left ventricular ejection function may not correlate with the long-term risk of death or transplantation in this subset of cardiomyopathy patients.

First answer to this question

It may arise from the European Study on Epidemiology and Treatment of Cardiac  Inflammatory Disease (ESETCID-trial) (6) were patients with autoreactive (virus-negative) myocarditis (AM) and an ejection fraction <45% were randomised for  6 months of  treatment with azathioprin (2mg/kg BW/day for 1 month and 0.85mg/kg BW/day for 5 month)  + prednisolone (1.25mg/kg BW/ for 1 month and 0.3mg/kg BW/day for 5 month) or placebo on top of their heart failure treatment and followed-up for up to 8 years. 3149 patients with dilated cardiomyopathy were screened, 103 pts (mean age 47± 9 years, 81 male, 22 female) with myocarditis and an ejection fraction <45% were randomised for ESETCID after informed consent and continuously follow-up. Endomyocardial biopsies were examined for lymphocytes & macrophages by immunhistochemistry (> 14 infiltrating cells/mm²), persistence of viral or bacterial genomes for Parvo B19, coxsackie-, influenza-, adeno-, cytomegalo-, HHV 6, EBV,  chlamydia and borrelia were excluded from the analysis.  56 patients with myocarditis were treated with verum, 47 patients with placebo.
MACE are defined as cardiac death, heart transplantation, ICD implantation or hospitalisation for cardiac decompensation.  Time to MACE is given in days to the event. Inflammation was eradicated in 63% in the treatment group, but it also vanished spontaneously in 40% in the placebo arm (p<0,05 when compared to 100% positive at initiation of therapy). After 12 months the Kaplan Mayer MACE curves began to diverge. At 4 years freedom from MACE was 50% in the verum and 40% in the placebo group.  Respective data at 8 years were 40% and 20% freedom from MACE. NYHA-association class and Minnesota Heart Failure Score improved in treatment and placebo arms to a similar extend. Ejection fraction by echo and radioventriculography improved in both arms with a trend for immunosuppression.
Independent from a therapy patients with no inflammation in the follow-up biopsy (n=45) showed  a better NYHA-class (p<0,05), ejection fraction and superior long term freedom from MACE than those with persistent inflammation.


The findings in the Frustaci trial are timely and have potential implications for the worldwide population of patients with dilated cardiomyopathy. The present study also has implications for further therapies such as immunoadsorption or plasmapheresis that may need to demonstrate favourable efficiacy and safety against inexpensive and widely available immunosuppressive agents for the treatment of chronic inflammatory cardiomyopathies. Maybe that the Esetcid-trail gives answers with regard to the clinical endpoints death or heart transplantation, as the patient population and treatment is comparable with the TIMIC-trial.
In the modern molecular era the infective agent-immune system-host interaction has become clearer leading to a better knowledge of the etiology of dilated cardiomyopathy. This may change the management of the disease in the future. One of the hopes is to discern the underlying dominant mechanism in a given patient to make a decision for the most promising therapy.


Andrea Frustaci, Matteo A. Russo and Cristina Chimenti. European Heart Journal published online June 25, 2009

1) Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J 2009, epup ahead of print, June 2009
2) Pankuweit S, Ruppert V, Maisch B. Inflammation in dilated cardiomyopathy. Herz 2004; 29(8):788-793.
3) Maisch B, Hufnagel G, Schönian U, et al., for the ESETCID Investigators. The European Study of Epidemiology and Treatment of Inflammatory Cardiac Disease (ESETCID). Eur Heart J 1995;S16:172–5.
4) Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindiger A, Bohm M. Predictors of outcome in patients with suspected myocarditis. Circulation 2008; 118: 639-648
5) Cooper LT. The heart is off: immunosuppression for myocarditis revisited. Eur Heart J 2009, epup ahead of print, June 2009
6) Maisch B, Pankuweit S, Koelsch S, Hufnagel G, Funck R, Grimm W, Sattler A for the ESETCID Investigators. Sequential Analysis of Immunosuppressive Therapy in Autoreactive Myocarditis - Sequential Analysis from ESETCID. 29th Congress of the European Society of Cardiology, Vienna, Eur Heart J 2008; 28: 603

Notes to editor

Presented by Dr. S. Pankuweit, University Hospital Marburg, Dept. of Cardiology, Baldinger Str., Marburg, Germany
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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