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Dilated cardiomyopathy (DCM) is a significant cause of morbidity and mortality worldwide.1,2 Noninvasive imaging plays a central role in the diagnosis, assessment of prognosis, and monitoring of therapy. Several reports have indicated an increased activation of inflammatory pathways in patients with idiopathic DCM, notably in the absence of systemic infection.3–6 Furthermore, inflammation may affect disease progression4 and thus serves as a therapeutic target in heart failure.4,5 Tissue edema is an integral component of inflammatory reaction in the myocardium and may exacerbate the extent of necrosis7 and interstitial fibrosis.8
Cardiovascular magnetic resonance (CMR) is a rapidly evolving technology increasingly used for noninvasive imaging of the expanding heart failure population. Tissue with a high content of protons bound to free water appears brighter on T2-weighted images due to stronger signal intensity feedback from the protons.9,10 Myocardial edema was introduced in the clinical setting as a specific marker for the acuity of myocardial injury in acute myocardial infarction.11,12 It was shown to improve the diagnostic accuracy of a comprehensive CMR protocol in patients with acute coronary syndrome.13 Edema imaging is also useful in other cardiac diseases such as sarcoidosis, acute rejection following cardiac transplantation,14,15 and stress-induced cardiomyopathy.16,17 Triple inversion breath hold sequence with short acquisition time (fast spin echo triple inversion recovery sequence [STIR]) is used in the clinical routine. These sequences have also demonstrated diagnostic value in patients with acute or chronic myocarditis.18–21 Furthermore, CMR studies allow evaluation of cardiac morphology, function, flow, perfusion, and myocardial edema with a single examination.9,22,23 The purpose of our study was to assess the frequency, and if present, regional distribution of myocardial edema in patients with chronic nonischemic DCM.
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In patients with nonischemic DCM we found evidence for global myocardial edema, which was correlated with global systolic dysfunction. Noninvasive imaging plays a central role in the diagnosis of DCM, in the determination of etiology and prognosis, as well as in monitoring therapeutic effects. An increased myocardial signal intensity in T2-weighted CMR images has been repeatedly associated with acute myocardial injury or acute inflammation as it reflects elevated intramyocardial free water content.11–13 We observed that patients with idiopathic DCM presented an increased myocardial T2 signal that might represent ongoing myocardial inflammation that must be further addressed by biopsy studies. This may have significant therapeutic and prognostic implications, because knowledge of the etiology of cardiac dysfunction in patients with heart failure impacts management and prognosis,25 yet is not identified in 50% of patients with DCM.25,26 Recent data suggest that many patients may be suffering from chronic myocardial inflammation due to persistent viral replication or autoimmune activation after a viral infection.3,25 Specific noninvasive tests for myocardial inflammation, however, have not been used in clinical settings. In the present study we found a significantly increased native and normalized signal intensity in T2-weighted CMR images in patients compared to controls. Moreover, we observed that this finding was moderately associated with lower EF. This new finding might be related to the known impact of edema itself on LV function.7,8
A substantial proportion (10%–34%) of patients with DCM may in fact suffer from viral myocarditis,27 and a substantial portion of patients with myocarditis and DCM represent different stages of an organ-specific autoimmune disease in genetically predisposed individuals.28,29 CMR is considered an important diagnostic tool for myocarditis,21,23 and an increased signal in T2-weighted images is a typical finding in patients with acute myocarditis.18–20,24 Importantly, in uncomplicated acute myocarditis, the signal normalizes over time,30 but signal abnormalities may persist in chronic myocarditis. Gutberlet et al21 also observed an elevated T2 ratio in 25 of 83 patients with suspected chronic myocarditis. T2 signals have not been examined routinely so far in patients with DCM. Thus, our new findings may reinforce the notion of chronic myocarditis as a possible cause of DCM in some patients.
There are reports of an increased inflammatory activation in patients with idiopathic DCM and no systemic infection.3–6 The observation that about 50% of our patients had evidence for global myocardial edema may indicate a different pathophysiologic situation such as chronic inflammation. This is in line with reports of chronic inflammation in 30% to 60% of patients with DCM.4–6 Larger and longitudinal studies with endomyocardial biopsies from patients with DCM are warranted to extrapolate on our preliminary findings and evaluate their diagnostic impact.
About two-thirds of our patients had small midmyocardial or subepicardial lesions of contrast enhancement. No patient had subendocardial or transmural scars as would be typical for coronary artery disease. There was no correlation between contrast enhancement and measurements of myocardial edema, indicating that edema may not necessarily be related to irreversible injury. In addition, there was no correlation with regional STIR values and the location of LGE. Myocardial LGE in DCM could indicate focal replacement fibrosis, and although the mechanisms underlying this have not yet been elucidated, a potential factor may be myocardial inflammation. The absence of a correlation between LGE and T2 measurements found in our study could be due to the fact that we found a more global elevated T2 pattern indicating global edema in these patients.
An increased myocardial signal intensity in T2-weighted CMR images (STIR) has been used to detect edema in acute myocardial infarction, acute rejection following cardiac transplantation, and sarcoidosis.11,12,14,15 These diseases were excluded by patient selection criteria. Undetectable small vessel ischemia would be another possibility for increased myocardial intensity, but it is unlikely in our patients because coronary artery disease was ruled out.
In a recent study by Voigt et al,31 23 adults with chronic DCM were examined by CMR and endomyocardial biopsy. Myocardial inflammation was confirmed by immunohistology using the Lake Louise Criteria in 12 patients (52.2%). They found a high sensitivity, specificity, and diagnostic accuracy of CMR to detect immunohistologically confirmed myocardial inflammation. Thus, there is a good agreement between that study and our results regarding the frequency of patients with DCM and myocardial edema: 52% in both studies. Both studies confirm that CMR is a promising tool for assessment of myocardial inflammation in patients with DCM.
Despite impressive medical advances, heart failure is still a significant cause of morbidity and mortality worldwide.1,2 Chronic idiopathic DCM is 1 of the main underlying diseases; yet, its pathophysiology and especially determinants of progression and remodeling are not thoroughly understood.32 Ongoing inflammatory processes may play an important role in the course of the disease; therefore, the noninvasive assessment of global myocardial edema as a diagnostic marker for inflammation may provide very useful information for a better understanding and management of these patients.9 Although precise mechanisms of how edema affects function, long-term tissue composition, and prognoses of the patients with DCM are to be elucidated further, it is known that increased stiffness and the reduced compliance of edematous myocardium affect diastolic and systolic function.9 Changes in intramyocardial pressure, and a high protein content of edema may promote myocardial fibrosis,8 which is extensive in patients with DCM.33,34
Our sample size is limited, and therefore our study may not have been powered to detect relationships of edema to clinical markers such as the severity of heart failure (NYHA class functional status). We did not perform biopsies to corroborate our results by ultrastructural and/or histological data. Biopsy data, however, reflect regional but not global changes and therefore are limited in their generalization. Patients with heart failure and controls had similar cardiac output and were clinically stable, suggesting that the patients had relatively mild disease. The mean NYHA class was 1.8, thus our findings cannot be extrapolated to patients with more severe disease or unstable conditions.