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European Journal of Heart Failure 2006 8(2):162-166; doi:10.1016/j.ejheart.2005.06.001
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© 2006 European Society of Cardiology

Myocardial biopsy findings and gadolinium enhanced cardiovascular magnetic resonance in dilated cardiomyopathy

Oliver Zimmermann*,1, Olaf Grebe1,2, Nico Merkle, Thorsten Nusser, Matthias Kochs, Magdalena Bienek-Ziolkowski, Vinzenz Hombach and Jan Torzewski

Department of Internal Medicine II—Cardiology, University of Ulm Robert—Koch—Str. 8, 89081 Ulm, Germany

* Corresponding author. Tel.: +49 731 500 0; fax: +49 731 500 24442. E-mail address: oliver.zimmermann{at}medizin.uni-ulm.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: In some patients suffering from dilated cardiomyopathy (DCM) magnetic resonance imaging (MRI) shows late gadolinium enhancement with variable distribution. Myocardial biopsies in DCM reveal a chronic myocardial inflammatory process in almost 50% and myocardial persistence of adenoviral or enteroviral genome in about 15% of the patients.

Aims: We prospectively investigated whether the pattern of late gadolinium enhancement correlates with myocardial biopsy findings.

Methods and results: 42 patients with DCM and 42 control subjects underwent contrast MRI. In the DCM group, endomyocardial biopsies were performed and evaluated for inflammation and viral genome.

None of the control subjects showed late gadolinium enhancement whereas in 29 DCM patients (69%) gadolinium enhancement was detectable (p<0.001). 21 of the DCM patients (50%) showed midwall septal enhancement, 7 patients (17%) showed a patchy distribution of hyperenhancement and 1 patient (2%) showed enhancement typical for ischemic heart disease. In myocardial biopsy analysis, 2 patients (5%) showed persistence of viral genome, 18 patients (43%) showed inflammation and in 22 patients (52%) neither virus nor inflammation was detected. The pattern of late gadolinium enhancement and myocardial biopsy findings were not significantly correlated (p=0.854).

Conclusion: MRI as a non-invasive technique cannot replace myocardial biopsy for the differential diagnosis of DCM.

Key Words: Dilated cardiomyopathy • Biopsy • Magnetic resonance imaging • Inflammation • Virus

Received January 25, 2005; Revised March 27, 2005; Accepted June 8, 2005


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Gadolinium enhanced MRI is a novel diagnostic tool in cardiovascular imaging representing a non-invasive method, which can be repeated without application of radiation or radioactive material.

Gadolinium is a hydrophilic contrast medium with low molecular weight (<1000 Da) that easily penetrates into the extracellular fluid space but not into living cells [1]. Thus, gadolinium accumulation is markedly increased in water-containing tissues and correlates with extracellular volumes. In damaged tissues, interstitial edema and loss of membrane integrity lead to accumulation and delayed gadolinium washout. This phenomenon is described as "late enhancement" [2].

Different myocardial patterns of late gadolinium enhancement have been described (e.g. transmural, subendocardial, intramural). Underlying cause, diagnosis and prognosis of cardiovascular disease have recently been correlated with patterns of gadolinium distribution [3-5]. McCrohon et al. [5] utilized late enhancement in order to distinguish between heart failure due to DCM and heart failure due to coronary artery disease (CAD). In acute myocarditis, contrast enhanced MRI visualizes the location, activity and the extent of inflammation [6,7].

DCM is defined as a myocardial disease of unknown etiology [8]. Interest has focused on two basic pathogenic mechanisms: Viral infection and inflammation. Viral infection in myocarditis may initiate an autoimmune response that causes DCM. Particularly entero- and adenoviruses have been recognized as an important cause of left ventricular dysfunction [9]. Abnormalities of humoral and cellular immunity have been demonstrated in patients with DCM [10-12]. The reported frequency of inflammatory infiltrates depends on patient selection and diagnostic criteria. Recently, molecular markers have been established for diagnosis of inflammation within the myocardium. Employing these markers in almost 50% of DCM patients a chronic myocardial inflammatory process is detectable [12].

In DCM, myocardial biopsy has emerged as an approach to differential diagnosis. According to biopsy results DCM can be classified in (a) chronic inflammatory cardiomyopathy, (b) DCM with persistence of viral genome and (c) none of these. Specific therapy based on biopsy results is under investigation [13,14]. Importantly, myocardial biopsy may be associated with severe complications like pericardial effusion and tamponade that can be fatal. Therefore, it would be of utmost interest to replace this invasive procedure by non-invasive techniques.

In this study we investigated whether results of gadolinium enhanced MRI correlate with endomyocardial biopsy findings in DCM and whether this technique may thus emerge as a novel avenue towards the replacement of myocardial biopsy by non-invasive techniques.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study and control population
42 patients with DCM admitted to Ulm University Medical Centre between 2001 and 2003 were included. Patients presented with the clinical symptoms of cardiac failure. Acute myocarditis was excluded by the overall interpretation of physical examination, lack of newly developed ECG changes and blood analysis (blood count, CRP, ESR, CK, Troponin I). Diagnostic evaluation included NYHA classification, ECG, echocardiography and cardiac catheterization. Left ventricular ejection fraction (EF) was evaluated by left ventriculography during cardiac catheterization, CAD was excluded by coronary angiography, and valvular and congenital heart disease were excluded. Also, patients with systemic hypertension were excluded. An EF value of ≤55% was used as a cut-off for the diagnosis of DCM. 42 age and sex matched subjects with unobstructed coronary arteries and normal left ventricular function served as controls.

2.2. Cardiovascular MRI protocol
MRI was performed on a 1.5T whole body scanner (Intera CV, Philips Medical Systems, Best, The Netherlands) within ±28 days to myocardial biopsy. To define the position and axis of the left ventricle, three short survey scans were performed. Left ventricular function was determined with ECG-gated cine images using a segmented k-space balanced TFE sequence (steady-state-free-precession) in short and long axis views in the true heart axis. Depending on the FOV in-plane resolution was between 1.5x1.8 to 2.3x1.8 mm with a slice thickness of 10 mm for the functional scans. Late enhancement (LE) images were performed 10-15 min after contrast (0.2 mmol/kg, Magnevist (Gadoteridol), Schering AG) using a 3D gradient spoiled turbo FFE sequence with a selective 180° inversion recovery prepulse. Inversion delay was individually adjusted to null myocardium using a 2D Lock-Locker sequence (SSFP, FOV 390 mm, Matrix 126, TE 2.6 ms, TR 5.4 ms). The left ventricle was covered with 20-22 slices from base to apex (slice thickness 5 mm, FOV 360-380, Matrix 256, in-plane resolution 1.4x1.5 mm2). Three additional long axis views (2-, 3- and 4-chamber) with a similar 2D-sequence (FOV 330, Matrix 256, in-plane resolution 1.3x1.3 mm2) were additionally performed. The typical examination time was 45 to 60 min. The MRI protocol could be completed in all patients without severe side effects.

2.3. Cardiovascular MRI analysis
Late Enhancement was qualitatively assessed by two blinded observers.

2.4. Myocardial biopsies
Analysis of myocardial biopsies was performed as described in detail [14]. In brief, six right ventricular (septal) endomyocardial biopsies were analyzed from each patient to reduce the sampling error. Histomorphological diagnosis of dilated cardiomyopathy was performed by examination of the following criteria: interstitial fibrosis, cellular infiltrates, cellular hypertrophy and myocardial cell degeneration.

Immunohistochemical analysis included staining for HLA I, HLA II, CD2, CD68 and CD54 [14]. A semiquantitative score system [staining intensity from no discernible to strongly abundant immunoreactivity (0 to +++)] was applied for HLA I, HLA II and CD54. CD2 and CD68 positive cells were counted under the light microscope (cells/mm2). Biopsies were classified as borderline inflammation (3 to 10 CD2 positive cells/mm2) or inflammatory cardiomyopathy (>10 CD2 positive cells/mm2). In samples with lymphocytic infiltrates, increased expression of adhesion molecules indicated a persistent inflammatory process within the entire sample.

Virological analysis for enteroviral RNA and adenoviral DNA was performed by PCR using extracted nucleic acid [14]. The GAPDH gene was used to demonstrate loading of intact DNA.

All procedures were performed in accordance with ethical standards and patients gave written informed consent. The investigation conforms with the principles outlined in the Declaration of Helsinki.

2.5. Statistical analyses
Statistical analysis was performed using SigmaStat version 2.0 software. Chi-Square test, t-test, One Way Analysis of Variance and Kruskal-Wallis One Way Analysis of Variance on Ranks were calculated as indicated. A p<0.05 was considered statistically significant. Tests were calculated unpaired and two-sided. Overall tests were performed first. If these tests revealed a p<0.05, pairwise tests were calculated.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Major characteristics of study and control population
Major characteristics of the study and control population are shown in Table 1. According to biopsy results, study patients were assigned to groups A, B or C as described recently [14]: (A) no virus and no inflammation (B) inflammation (borderline inflammation and inflammatory cardiomyopathy) but no virus (C) virus with or without inflammation. 22 patients (52%) were assigned to group A, 18 patients (43%) to group B and 2 patients (5%) to group C. Within group C, the only viral genome detected was coxsackievirus B. LVEF at the time of myocardial biopsy was significantly lower in the study population (p<0.001). The median time from first diagnosis to myocardial biopsy was 0 (0-120) months for group A, 0 (0-120) months for group B and 60 (48-72) months for group C (for all DCM patients 0 (0-120) months). As first diagnosis of DCM in patients was not always performed in our department we evaluated this period retrospectively using medical records and available folders.


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  		Table 1 Major characteristics of study and control population

 
3.2. Correlation of late gadolinium enhancement and myocardial biopsy findings
Fig. 1 shows different patterns of late gadolinium distribution within the myocardium. Table 2 shows the correlation between patterns of late gadolinium enhancement and myocardial biopsy findings. In accordance with McCrohon et al [5] we distinguished (1) absent abnormal gadolinium enhancement (2) subendocardial or transmural enhancement following a coronary supply territory (i.e. "CAD type" as a pattern typical for coronary artery disease) (3) midwall striae (longitudinal septal intramural enhancement) which is often a very subtle finding and (4) the patchy pattern (focal enhancement not following the coronary supply).


Figure 1
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  		Fig. 1 Different distribution patterns of gadolinium within the myocardium, top left: intramural; top right: transmural; bottom left: subepicardial; bottom right: healthy myocardium (control group).

 


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  		Table 2 Correlation between late gadolinium enhancement and myocardial biopsy findings

 
None of the control subjects showed late enhancement whereas in 29 DCM patients (69%) enhancement could be detected (p<0.001). No statistically significant differences were observed for the prevalence of late gadolinium enhancement within groups A-C (p=0.768). Furthermore, no statistically significant differences were detected for the patterns of gadolinium distribution between groups A to C (p=0.854). Additionally, a significantly higher prevalence could be detected for pericardial effusion (p<0.001) and subendocardial first pass perfusion abnormalities (p=0.026) in the study group.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Two major observations were made in this study:

  1. Late gadolinium enhancement is a typical feature found by cardiac MRI in DCM patients, whereas healthy hearts do not show late gadolinium enhancement.
  2. The pattern of gadolinium enhancement in DCM patients is not correlated with myocardial biopsy findings.

In DCM, the underlying cause of disease (i.e. inflammatory activity or chronic viral infection) may be useful for the introduction of a specific therapy with immunosuppressive or antiviral agents [13,14]. Although the value of these therapies is not yet proven definitively, they are currently under intense investigation. So far, myocardial biopsy is the only approach to differential diagnosis. It would be beneficial to replace this invasive procedure, which may be associated with severe complications, by non-invasive methods. We thus investigated whether inflammatory or viral DCM shows a specific pattern in late gadolinium enhanced MRI. Although we found that late enhancement is a typical feature in DCM (as compared to healthy hearts), no correlation and no specificity were found for the pattern of late gadolinium enhancement and biopsy findings.

Few reports have described labeling techniques for MRI-detection of mammalian cells in vivo [15-17]. Monoclonal antibodies containing metal-binding domains for specific antigen detection have been reported [17]. Such specific detection of inflammatory cells or viral epitopes by MRI may provide a novel approach to non-invasive differential diagnosis in DCM.

Recently, Mahrholdt and colleagues [7] demonstrated in 32 patients with acute myocarditis that inflammatory lesions are detectable by late gadolinium enhanced MRI and, in this population, were predominantly located in the lateral free wall of the left ventricle. MRI-directed myocardial biopsy in regions of late enhancement revealed active myocarditis more often than in regions without enhancement. In our study of DCM (not acute myocarditis), myocardial biopsies were taken from the right ventricular septum, where late enhancement was predominantly located. In general, myocardial biopsy analysis shows that inflammation in DCM is less pronounced than in acute myocarditis.

In summary we demonstrate that in DCM, late gadolinium enhancement is an often subtle but common feature. The pattern of late gadolinium enhancement does not correlate with myocardial biopsy findings. Thus, endomyocardial biopsy offers additional information and can currently not be replaced by contrast enhanced MRI for differential diagnosis of DCM.


   Acknowledgements
 
We gratefully acknowledge the staff of the catheterization laboratory of Ulm University.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} Supported in part by the Deutsche Herzstiftung.

1 These authors contributed equally. Back

2 Current address. Department of Cardiology, EVK Düsseldorf, Kirchfeldstraβe 40, 40217 Düsseldorf, Germany. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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  6. Friedrich M.G., Strohm O., Schulz-Menger J., Marciniak H., Luft F.C., Dietz R. Contrast media-enhanced magnetic resonance imaging visualizes myocardial changes in the course of viral myocarditis. Circulation (1998) 97:1802–1809.[Abstract/Free Full Text]
  7. Mahrholdt H., Goedecke C., Wagner A., et al. Cardiovascular magnetic resonance assessment of human myocarditis: a comparison to histology and molecular pathology. Circulation (2004) 109:1250–1258.[Abstract/Free Full Text]
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  14. Zimmermann O, Kochs M, Zwaka TP, et al. Myocardial biopsy based classification and treatment in patients with dilated cardiomyopathy. Int J Cardiol in press.
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