Objective: Based upon epidemiological studies, male gender and younger age are risk factors for developing fatal myocarditis. The impact of age and gender on myocardial injury pattern in acute myocarditis, however, is not well understood. In patients with clinically acute myocarditis, this study sought to characterise the relation between patient age and gender and the extent of myocardial involvement using cardiovascular magnetic resonance (CMR) imaging. CMR markers for oedema, inflammation and fibrosis defined myocardial involvement.
Design, Setting and Patients: 65 patients (42 years old (SD 15), 41 male) with clinically acute myocarditis were assessed. Using standard methods, T2-weighted and contrast-enhanced T1-weighted (early and late enhancement) CMR images were acquired. T2 images were visually and quantitatively assessed for oedema. Early enhancement images were quantified for inflammation, as was regional fibrosis in late enhancement images. Data were analysed for groups of age (>40, <40 years) and gender.
Results: 62% of all patients had evidence of regional oedema, which was more prevalent in patients below 40 years of age (80.7% vs 51.3%, p<0.05), as was myocardial fibrosis (76.9% vs 48.7%, p<0.05). However, early enhancement was more frequently found in patients above 40 years (84.2% vs 61.5%, p<0.05). Men were twice as likely as women to demonstrate myocardial fibrosis (73.2 vs 37.5%, p<0.01).
Conclusion: In patients with clinically acute myocarditis, myocardial fibrosis was more frequent in men and in patients younger than 40 years. Injury sustained in younger patients appears to be more regional and more severe, as indicated by a higher incidence of irreversible injury.
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Myocarditis is defined as myocardial inflammation mostly resulting from viral infections.1 It has been shown that younger individuals are at a greater risk of death and heart transplantation ensuing from myocarditis,2 and show greater incidences of fatal myocarditis.3 4 Interestingly, men are also at higher risk of fatal myocarditis.3 4 Whether there are gender or age-related differences in the pattern of myocardial involvement is not well understood.
Cardiovascular magnetic resonance (CMR) based tissue characterisation allows for non-invasive visualisation of tissue markers of myocarditis5 including oedema,6 inflammation7 8 and fibrosis.9 The presence, regional distribution and extent of these markers may not only provide important diagnostic, but also prognostic, information. This is suggested by findings that indicate that a persisting presence of CMR markers for inflammation correlated with a lack of functional recovery;10 areas of fibrosis were found to be potential arrhythmogenic substrates11 and oedema was associated with conduction disturbances.12
We hypothesised that in myocarditis, younger age and male gender are associated with more severe injury to the heart as defined by CMR markers for inflammation and scar.
For the duration of this study (32 months), 302 patients were referred to our institution with a clinical suspicion of myocarditis. Of these, 65 (42 years old (SD 15), 41 male) patients met the inclusion criteria. All patients had to meet clinical criteria as well as CMR findings. Clinical criteria included recent symptoms, evidence of myocardial involvement, as defined by clinical criteria listed in box 1, and exclusion of coronary heart disease. The local ethics committee provided approval for this investigation.
Box 1 Inclusion criteria
Recent cardiac or viral symptoms.
New onset ECG changes or elevated cardiac enzymes or wall motion abnormalities in echocardiography.
Negative coronary angiogram or ischaemic stress test or less than two risk factors for heart disease.
To assess for age and gender-dependent effects, patients were further categorised using a cut-off value of 40 years, and gender, respectively. This threshold was selected as it has been shown that the age-dependent incidence of fatal myocarditis varies with this threshold.4
Image acquisition was performed on a 1.5-T whole-body system (Avanto, Siemens Medical Solutions, Erlangen, Germany). A 12-element cardiac phased-array surface coil was utilised for all sequences except T1-weighted early enhancement, for which a body coil was used. Localisers and left-ventricular functional assessment was performed using steady-state free-precession images. A triple inversion-recovery T2-weighted sequence (short-T1 triple inversion recovery) with suppression pulses for blood flow and fat was utilised to assess oedema in three short axis slices, covering the base, mid and apex of the heart.6 To correct for inhomogeneity of the phased array coil’s reception field, a signal intensity correction algorithm was used. T1-weighted turbo spin echo images were acquired before and during the first 3 minutes after an intravenous bolus of 0.1 mmol/kg Gd-DTPA was administered. Five to 10 minutes after intravenous administration of the contrast agent, late enhancement images were acquired in short axis slices covering the entire left ventricle, using a phase-sensitive inversion-recovery gradient echo sequence with an in-plane resolution of 1.48 × 1.48 mm2, and individually adjusted TI to optimise nulling of apparently normal myocardium.
For all quantitative analyses, certified CMR image evaluation software was used (cmr42, Circle Cardiovascular Imaging Inc, Calgary, AB, Canada). Standard methods of left-ventricular functional analysis were performed by manually tracing endocardial and epicardial contours. Global myocardial oedema was assessed by normalised signal intensity quantification in T2-weighted images, with manually traced endocardial and epicardial contours of the entire visible myocardium and skeletal muscle in the same slice. To exclude slow-flow as well as partial volume artifacts, contours were carefully traced to exclude epicardial and endocardial borders. The region of interest in skeletal muscle was identified in steady-state free-precession images at the same slice position. Myocardial signal intensity (SI) was divided by the SI of skeletal muscle. A ratio greater than or equal to 2 was considered to be reflective of the presence of global myocardial oedema.6 Focal areas of visually apparent high SI in the T2 images were considered to demarcate regional myocardial oedema, after the possibility of artifacts was excluded. Regions of increased signal intensity that did not follow the contour of the myocardium, or crossed endocardial or epicardial surfaces were considered to be representative of image artifacts.
As another criterion for tissue inflammation, early enhancement reflecting hyperaemia and capillary leakage was assessed by tracing endocardial and epicardial contours in T1 images, which were acquired before and over the first 3 minutes after contrast injection. A region of interest was traced within normally appearing skeletal muscle. All contours were traced in pre-contrast images, and copied onto post-contrast images; necessary adjustments were made to exclude cavitary volume. The myocardial enhancement (%SI increase post vs pre-contrast image) was normalised to the enhancement of the skeletal muscle. If the SI ratio was greater than or equal to 4, it was considered to be reflective of the presence of myocardial inflammation.7 8
Late enhancement images were assessed qualitatively and quantitatively. Qualitative analysis was performed by a consensus read between two readers (OS and MSC) for visual evidence for fibrosis, in all patients. In patients who had visual evidence of late enhancement, further quantification of fibrosis was performed by tracing endocardial and epicardial contours in slices covering the entire left ventricle. Papillary muscles and trabecular tissue were excluded from the analysis. For defining normal myocardium, a region of interest was traced in an apparently normal (ie, low-SI) area. An automated computer-aided threshold detection set at 5 SD above the mean SI of normal myocardium was utilised to identify regions of myocardial fibrosis.13 The extent of fibrosis was defined as the percentage of fibrotic myocardium in complete short axis slices covering the entire left ventricle.
All statistical analyses were performed using SPSS 16 for Macintosh. Data are presented as mean (SD). The normal distribution of data was assessed with a one-sample Kolmogorov–Smirnov test. Independent samples and non-parametric t tests, as well as χ2 tests were used to evaluate differences between groups. A p value of less than 0.05 was considered to define statistically significant differences.
The duration between the request for a CMR scan to the actual scan was utilised as a surrogate parameter for estimating the duration of symptomatic myocarditis. This information was available in 58 patients. There were neither age (age <40 years 5.0 days (SD 12.9) vs age ⩾40 years 11.2 days (SD 19.0), p = 0.18), nor gender-related (male 7.4 days (SD 16.5) vs female 11.0 days (SD 18.0), p = 0.44) differences between groups for the duration of symptomatic myocarditis. The clinical presentation of symptomatic myocarditis included heart failure (n = 12), palpitations (n = 14), shortness of breath (n = 37), recent viral illness (n = 35), elevated cardiac enzymes troponin or creatinine kinase (n = 40), as well as chest pain (n = 43).
The diagnostic image quality of T2-weighted images for the visualisation of myocardial oedema was obtained in all patients. In one patient, early enhancement could not be assessed due to non-diagnostic image quality. Three patients with visual evidence of late enhancement experienced discomfort during the scan, so only basal mid and apical myocardial slices were acquired. In these patients, the extent of fibrosis could not be quantified. Global measures of left-ventricular function segregated by age and gender are presented in tables 1 and 2. The range of left-ventricular ejection fraction for the study population was 63%, with a minimum of 13% and a maximum of 76%.
Overall, 35 patients presented with global or regional oedema in addition to late enhancement, 17 presented with only global or regional oedema and four presented with fibrosis only. The presence of troponin and/or creatinine kinase elevation was associated with myocardial fibrosis (p = 0.01) and regional oedema (p = 0.012).
CMR markers and age
Relationship between patient age and myocardial oedema
The oedema ratio, reflecting global oedema, did not differ between those below 40 years (1.96, SD 0.47) or those above 40 years (1.93, SD 0.42; p = 0.80). In addition, there were no differences in the proportion of individuals in either age group who were positive for oedema, based upon the previously reported cutoff (p = 0.52) (fig 1(A)).
Focal regions of increased signal intensity reflecting regional myocardial oedema were visualised in 62% (41) of the patients. The proportion of individuals younger than 40 years had a predilection for regional oedema (80.8% vs 51.3%, p<0.05) (fig 1(A)).
Relationship between patient age and myocardial inflammation
Although the early enhancement ratio did not differ significantly between younger (6.27, SD 4.4) and older (6.56, SD 3.4) patients (p>0.05), 84.2% of older patients were positive for early enhancement, compared with only 61.5% of younger patients (p<0.05) (fig 1(A)).
Relationship between patient age and myocardial fibrosis
A far greater proportion of younger patients had visual evidence of myocardial late enhancement (76.9%) compared with 48.7% of older patients (p<0.05) (fig 2). There was no difference in the extent of fibrosis between groups (18.0% (SD 7.3) vs 16.5% (SD 12.0), p>0.05).
CMR markers and gender
Relationship between gender and myocardial oedema
The T2 ratio reflecting global myocardial oedema did not differ between women and men (2.05 (SD 0.45) vs 1.88 (SD 0.43), p = 0.15), although there was a trend for global oedema to be more prevalent in women than men (62.5% vs 39.0%, p = 0.058) (fig 1(B)). The proportion of patients presenting with regional oedema did not differ between the two groups (p = 0.08).
Relationship between gender and early enhancement
There were no gender differences for the ratio of early enhancement between the two groups (6.49 (SD 4.1) vs 6.36 (SD 3.3), p>0.05). Similarly, there was no difference between genders in terms of the proportion of patients presenting with early enhancement (29/41 men (72.5%) vs 19/24 women (79.2%), p>0.05) (fig 1(B)).
Relationship between gender and myocardial fibrosis
Thirty out of 41 men (73.2%) and nine out of 24 women (37.5%) had evidence of the presence of fibrosis. As such, men were two times more likely to present with visual evidence of myocardial fibrosis (p<0.01) (fig 3). If present, the amount of fibrosis did not differ between groups (18% (SD 8%) in men vs 14% (SD 16) in women, p = 0.33).
Utilising CMR-based surrogate markers for myocardial inflammation, we provide evidence for the age and gender-related predominance of different tissue characteristics in patients with clinically acute myocarditis. Our findings demonstrate that younger patients have a greater incidence of regional oedema and myocardial fibrosis. On the other hand, older patients were more likely to have evidence of more diffuse myocardial inflammation. Men were more prone to presenting with fibrosis. These observations confirm and extend previous experimental and clinical findings.
In our study cohort, we found a greater propensity for men and younger individuals to develop both myocardial fibrosis and regional oedema. Epidemiological studies have identified both of these groups as being at a greater risk of developing fatal myocarditis.3 In fact, young age has been shown to be a predictor of death and transplantation in patients with biopsy-confirmed myocarditis.2 Similarly, the incidence of fatal myocarditis is greatest for individuals below 40 years of age.4 Compared with women, men also present with a greater incidence of death from myocarditis. These epidemiological findings may be related to tissue characteristics, in which regional oedema and an increased incidence of fibrosis results in reduced patient prognosis.
The age and gender-related disparity observed in our study and previous epidemiological findings are likely to be ensuing from the mechanics of immunity. We found that whereas younger patients had regional myocarditis typified by regional oedema, older patients showed evidence of more diffuse inflammation. In addition, older patients had a significantly lower ejection fraction than younger patients. It may be the case that global diffuse myocardial inflammation may lead to depressed cardiac contractility, and thus reduced ejection fraction. Given that younger patients predominantly presented with regional injury, ejection fraction may not have been reduced because of the regional nature of this process. Any explanation remains speculative, but it is conceivable that a higher total cumulative exposure to viral antigens in older individuals may lead to a different immune response and thus be responsible for this difference. Hori et al14 have shown that, in addition to an antigen responsible for clinically symptomatic myocarditis, there is evidence of exposure to other antigens. It has been found that healthy individuals have evidence of neutralising antibodies to Coxsackie B viruses,15 indicating previous exposure to immunological transformation. Furthermore, in mice, repetitive exposure to an antigen results in more pronounced global cardiac inflammation.16 17 Therefore, older patients may present with global myocardial involvement due to previous exposure to antigens. Similarly, murine models have demonstrated that male gender is associated with proinflammatory activation18 19 and increased myocardial inflammation.
There is evidence that tissue pathology such as oedema and fibrosis is relevant to outcome. In patients with biopsy-confirmed myocarditis, oedema is associated with conduction abnormalities such as complete atrioventricular block and increased QRS duration.12 Furthermore, conduction abnormalities were found to be more prominent in patients who presented with myocardial necrosis, as visualised by antimyosin scintigraphy.20 More recently, it has been shown that in non-ischaemic cardiomyopathy,21 myocardial fibrosis is a strong predictor of adverse cardiac outcomes. The extent of fibrosis observed in our study cohort for patients with visual evidence for late enhancement was 17.2% (SD 8.8), and may be explained by the fact that our patients were clinically symptomatic and may have had a more severe bout of myocarditis. In addition, visual evidence of myocardial fibrosis was related to elevated cardiac enzymes troponin and/or creatinine kinase, suggesting that perhaps the myocarditis was more necrotising in these individuals.
These considerations may also provide an explanation as to why myocarditis is generally less frequently observed in the elderly population.
Specific treatment of acute myocarditis remains a challenge. Current therapeutic approaches are mostly limited to supportive therapy, and previous trials on the use of specific antiviral or immunosuppressive therapy provided conflicting data.22 23 However, it may be conceivable that the outcomes of these trials would have differed if regional patterns of inflammation or injury and the presence of specific patient populations with a specific risk profile were taken into account. It may be the case that therapeutic interventions might be more advantageous in the inflammation patterns we observed in younger patients and men, whereas in milder forms of myocardial involvement (as observed in older patients and women), supportive therapy may suffice. Clinical studies would have to test such hypotheses. In both research and clinical scenarios knowledge on tissue characteristics assessed by CMR may provide important diagnostic and prognostic information.
Limitations and technical considerations
We did not perform serological tests to determine viral titres, nor myocardial biopsy to determine the aetiology of myocarditis,24 and thus could not perform immunohistology.25 Patient selection may have influenced our results. It has been observed that myocarditis may progress from a focal to diffuse injury process, with the age of illness having important implications. In our study cohort, the exact duration of myocarditis could not be determined, as this information was not systematically available. As such, we estimated the duration of symptomatic myocarditis with the length of time between the request for CMR to the actual scan. We felt that this was a strong and reliable marker, as it is based upon a physician’s interpretation of clinical history and disease severity. However, the possibility of a referral bias dependent upon age and gender differences among patients cannot be excluded. Nor can it be excluded that some patient groups may seek medical therapy sooner than others. We do not have follow-up data and thus cannot comment on the possible prognostic relevance of these findings.
In patients with clinically acute myocarditis, myocardial fibrosis was more frequent in men and in patients younger than 40 years. Injury sustained in younger patients appears to be more regional and more severe, as indicated by a higher incidence of irreversible injury.
The authors are greatly appreciative of the technical expertise of Sherri-Lee Rinella, Terri Bomak and Loreen Thon with image acquisition.
Funding MSC is a recipient of a Health Research Studentship Award from the Alberta Heritage Foundation for Medical Research.
Competing interests MGF is shareholder and scientific advisor to Circle Cardiovascular Imaging Inc, Calgary, the manufacturer of the software used for the evaluation. The other authors have no conflicts of interest.
Provenance and peer review Not commissioned; externally peer reviewed.
Ethics approval The local ethics committee provided approval for this investigation.