Echocardiographic findings in fulminant and acute myocarditis

Study population

Seven hundred fifty patients underwent endomyocardial biopsy at our institution over a seven-year period as part of a comprehensive evaluation of unexplained cardiomyopathy. Seventy-two of 750 patients (9.6%) were diagnosed as having myocarditis or borderline myocarditis by the Dallas Criteria (3). This group did not include patients who had evidence of myocarditis in the setting of a systemic process such as human immunodeficiency virus infection or sarcoidosis. Patients were further classified as having acute, fulminant, chronic active or chronic persistent myocarditis, using our previously reported classification system (7). Using these criteria, 43 patients were classified as having acute myocarditis and 11 as having fulminant myocarditis. These 54 patients were the subjects of this study.

Echocardiography

Standard two-dimensional echocardiography was performed at the time of presentation and after six months. Baseline echocardiograms for each patient were evaluated. Follow-up echocardiograms at six months for seven patients with fulminant myocarditis and 25 patients with acute myocarditis were evaluated. Of the patients with no follow-up echocardiograms available, two patients with fulminant (18%) and four patients with acute myocarditis (9%) died. Two patients with fulminant (18%) and 14 with acute myocarditis (32%) were lost to follow-up. For each echocardiogram, left ventricular diastolic dimension (LVEDD) and maximal septal thickness were measured by M-mode in the parasternal long axis view using the leading-edge to leading-edge method. Percentage fractional shortening (%FS) was calculated in a standardized manner (9).

Endomyocardial biopsy

All patients underwent endomyocardial biopsy using a right internal jugular vein approach and a Stanford-Caves or disposable bioptome. At least four specimens were taken from the right ventricular septum and immediately placed in either 10% formalin for light microscopy or 3% glutaraldehyde for electron microscopy. Each formalin-fixed specimen was stained with hematoxylin-eosin and examined at at least four levels by an experienced cardiac pathologist (R.H.H., G.M.H.). The presence of myocarditis or borderline myocarditis was determined according to the Dallas Criteria (3) and graded as mild, moderate, or severe blinded to patient classification. The diagnosis of myocarditis was confirmed by immunohistochemical staining for T-lymphocytes.

Hemodynamics

After endomyocardial biopsy, all patients underwent right heart catheterization using a balloon-tipped, flow-directed thermodilution catheter. Measurements of cardiac output were obtained in triplicate with <10% variability between measurements. Cardiac index, LV stroke work index, systemic vascular resistance index and pulmonary vascular resistance index were calculated using standard formulas.

Statistical analysis

All values are reported as mean ± standard deviation. Measurements between groups at baseline were compared using the Student t test. Two-way repeated measures analysis of variance was used for assessing the interaction between type of myocarditis and changes at baseline and six months, with time as the within patient variable and type of myocarditis as the between patient variable (Stata 6.0, College Station, Texas). A two-sided p value < 0.05 was considered statistically significant.

Patient characteristics

The initial clinical characteristics of the patients with fulminant and acute myocarditis are shown in Table 1. By definition, the baseline characteristics differed between the two groups. All patients with fulminant myocarditis reported a flu-like prodrome or fever in the four weeks proceeding the onset of cardiac symptoms, compared with 21% in the acute myocarditis group. Patients with fulminant myocarditis generally had the abrupt onset of symptoms within two weeks of presentation, whereas symptom onset in those with acute myocarditis was indistinct (dated to a period of weeks to months). All patients classified as fulminant myocarditis had New York Heart Association class III or IV heart failure symptoms, while functional limitation in those with acute myocarditis was more variable.

Echocardiography

Echocardiographic measurements at baseline and at six months are shown in Figures 1 and 2. ⇓⇓ Both groups had markedly decreased LV systolic function at baseline that was of similar magnitude (%FS = 17 ± 7% for acute vs. 19 ± 4% for fulminant, p = NS, normal 28% to 41%). Patients with fulminant myocarditis had significantly less ventricular dilation at baseline (LVEDD = 5.3 ± 0.9 cm vs. 6.1 ± 0.8 cm, p < 0.01, normal < 5.5 cm) but greater septal thickness (1.2 ± 0.2 cm vs. 1.0 ± 0.1 cm, p = 0.01) than patients with acute myocarditis.

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Figure 1

Echocardiographic findings in patients with fulminant and acute myocarditis at baseline and six months. (A) Fractional shortening, (B) left ventricular end-diastolic dimension, (C) septal thickness. ∗p < 0.01 vs. acute; †p < 0.01 for interaction between time and type of myocarditis.

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Figure 2

Two-dimensional echocardiograms from patients with fulminant and acute myocarditis at presentation. The top panels show the parasternal long axis (A) and short axis (B) views of a 20-year-old man with fulminant myocarditis who presented after five days of a viral syndrome followed by acute hemodynamic collapse. Note the severe ventricular thickening (septal thickness 2.1 cm) but small ventricular cavity size (LVEDD 2.5 cm). After hemodynamic support with intravenous inotropic agents and a left ventricular assist device, this patient recovered near normal left ventricular function. The bottom panels show parasternal long axis (C) and short axis (D) views from a 19-year-old man with acute myocarditis who presented with three weeks of fatigue, fevers and the gradual onset of dyspnea on exertion. Note the decreased ventricular thickness (septal thickness = 0.6 cm) and marked dilated left ventricular cavity (LVEDD = 6.9 cm). At six month follow-up, LVEDD had increased to 8.0 cm, and the patient was awaiting cardiac transplantation. LVEDD = left ventricular diastolic dimension.

At six months, the patients with fulminant myocarditis showed a marked improvement in the %FS (30 ± 8%, p < 0.01 vs. baseline), resulting in normal LV systolic function. In contrast, patients with acute myocarditis showed no significant improvement in fractional shortening at six months compared with baseline (%FS = 19 ± 7%, p = NS vs. baseline). The interaction between type of myocarditis and time for fractional shortening was highly significant (p < 0.01). Complete normalization of ventricular function was significantly more likely in patients with fulminant myocarditis (57%) than in those with acute myocarditis (20%, p = 0.05).

There was a trend towards greater resolution of septal thickening in the fulminant group (from 1.2 ± 0.2 cm at baseline to 1.0 ± 0.1 cm at six months) than the acute group (1.0 ± 0.1 cm at both baseline and six months), but this did not reach statistical significance (p = 0.095 for the type of myocarditis/time interaction). Left ventricular diastolic dimension at six months remained significantly smaller in the fulminant group than it did in the acute group (5.1 ± 0.6 cm vs. 6.2 ± 0.9 cm, p < 0.01). Left ventricular diastolic dimension did not significantly changed in either group between baseline and six months (p = 0.63 for type of myocarditis/time interaction).

Histology

The histologic characteristics of endomyocardial biopsy specimens for study patients are shown in Table 2. All patients in the study had either histologic myocarditis (81%) or borderline myocarditis (19%) on endomyocardial biopsy as criteria for study entry. All patients in the fulminant group had histologic myocarditis by the Dallas Criteria. In the acute group, myocarditis was diagnosed in 77% of patients, with the remainder having borderline myocarditis. By definition, the degree of inflammation seen on endomyocardial biopsy specimens was substantially greater in patients with fulminant myocarditis than those with acute myocarditis (Fig. 3).

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Figure 3

Endomyocardial biopsy specimens from patients with fulminant (A) and acute (B) myocarditis. Fulminant myocarditis was characterized by more extensive and diffuse lympocytic infiltration and myocyte necrosis than acute myocarditis (hematoxylin-eosin stain, original magnification × 400).

Hemodynamics

Hemodynamic measurements at the time of endomyocardial biopsy for both groups are shown in Table 2. Patients with fulminant myocarditis had more severe hemodynamic compromise at presentation than those with acute myocarditis. Mean arterial pressure and systemic vascular resistance were both significantly decreased in the fulminant group when compared with those with acute myocarditis (p < 0.01 for each), despite substantially higher use of intravenous inotropic agents in patients with fulminant myocarditis (64% vs. 5%). Heart rate, right atrial pressure, pulmonary artery mean pressure and pulmonary capillary wedge pressure were all significantly higher in the fulminant myocarditis group than they were in the acute group (p < 0.03 for each).

Prior studies of echocardiography in myocarditis

Previous studies of echocardiography in myocarditis have demonstrated a variety of echocardiographic findings. In addition to systolic dysfunction (10,11), regional wall motion abnormalities (10), diastolic dysfunction (12) and changes in echocardiographic image texture (13) have been reported. These studies have not attempted to distinguish clinical syndromes within the spectrum of patients with myocarditis. Additionally, some reports have utilized clinical rather than histologic criteria in making the diagnosis of myocarditis, potentially confounding their results by including patients who may not have had histologic evidence of myocarditis. We have shown the utility of echocardiography in classifying patients with histologically proven myocarditis based on LV morphology at presentation.

Data from several previous studies are consistent with our findings. Pinamonti and colleagues (10) described echocardiographic findings in 41 patients with histologically proven myocarditis and found LV dysfunction in 69%, primarily with little to no dilation of the LV cavity (10). They also noted four patients in their series with transient “LV hypertrophy” in the setting of myocarditis. In two of these patients, ventricular thickening was associated with dramatic improvement in LV function. Transient “LV hypertrophy” associated with myocarditis has also been reported by Hauser and coworkers (14) in a 28-year-old woman with sudden onset of severe heart failure (14). Spontaneous resolution of LV thickening in this patient was associated with normalization of systolic function and clinical recovery. It is likely that these cases represent examples of the fulminant type of myocarditis as described in this report. Although the degree of LV dilation is often related to the severity and duration of heart failure, our data demonstrate that severe systolic dysfunction may occur in the absence of significant ventricular dilation in patients with fulminant myocarditis. Left ventricular dysfunction without significant cavity dilation has also been reported as a variant of idiopathic DCM in patients without myocarditis, and both progression to DCM and normalization of systolic function have been reported (15).

Potential mechanisms

The increased LV thickness in fulminant myocarditis is likely due to the greater inflammatory response seen on endomyocardial biopsy in these patients. Interstitial edema may contribute to both thickened ventricular walls and decreased ventricular contractility in this disorder. The contrast between LV morphology seen on echocardiography in fulminant and acute myocarditis is demonstrated in Figure 2, showing dramatically differing echocardiographic findings between fulminant and acute myocarditis. The explanation for the differences in the presentation and natural history of these disorders is unknown. These differences may be influenced either by the virulence or inoculum of the causative viral agent or by host factors such as genetic predisposition (16–18). It is possible that a more vigorous immune response in patients with fulminant myocarditis is responsible for both the more severe initial presentation and the improved outcome at six months.

Outcomes in myocarditis

Widely variable outcomes in patients with myocarditis have been described. A long-term follow-up study by Quigley and colleagues (6) confirmed the variable prognosis in patients with this disorder, with some patients regaining normal ventricular function and others progressing to DCM. This study did not find a correlation between the degree of LV dysfunction at presentation and subsequent echocardiographic or clinical outcome. Similar findings were reported by Dec and coworkers (1), who described 18 patients with acute onset of cardiomyopathy and histologic myocarditis, of whom some made complete recovery while others progressed to DCM. Notably, the two patients in this study with endomyocardial biopsies demonstrating a “diffuse, dense inflammatory infiltrate” on histologic examination both recovered LV function, whereas patients with a focal pattern of myocarditis had a prognosis similar to patients with idiopathic DCM. These data are in agreement with our findings, in which patients with a more severe inflammatory infiltrate (i.e., those with fulminant myocarditis) had a much greater propensity for recovery of normal ventricular function. Echocardiographic criteria that predict outcome in patients with myocarditis have not been well-established. Mendes and colleagues (19) reported 23 patients with biopsy proven myocarditis in whom the presence of right ventricular dysfunction by echocardiography predicted worse clinical outcome. We have examined the differences in echocardiographic features between patients with differing clinical syndromes and myocarditis and found substantial morphologic differences at presentation that may predict subsequent recovery of ventricular function.

Study limitations

This study has several potential limitations. The number of patients was relatively small, particularly in the group with fulminant myocarditis. Echocardiographic follow-up was incomplete in both the acute and fulminant myocarditis groups, reducing the power of our conclusions regarding the changes in morphology between baseline and six months. Still, this study represents the largest systematic study of echocardiographic findings in patients with biopsy proven myocarditis. Our study was retrospective, but the classification into categories of myocarditis was done prospectively. All diagnoses of myocarditis were based on accepted histologic criteria. Although inflammatory cell infiltrates have been demonstrated in some cases of idiopathic DCM (20), 81% of our cases showed frank myocarditis, and we used immunohistochemical staining for T-lymphocytes to confirm the diagnosis in all cases of borderline myocarditis.

The use of immunosuppression was not controlled in this study. Two of 11 patients with fulminant myocarditis and 30 of 43 patients with acute myocarditis received some type of immunosuppressive therapy, generally corticosteroids. While it is possible that the greater use of immunosuppressive therapy in the patients with acute myocarditis may have led to worse echocardiographic outcomes in this group, this does not seem to be a plausible explanation for our findings. Our previous experience has suggested that patients with fulminant myocarditis, despite their severe clinical presentation, improve without immunosuppression. The utility of immunosuppression in acute myocarditis is unclear, but a consistent benefit was not seen in the Myocarditis Treatment Trial (21). Given the observational methods used in this study, no conclusions can be drawn regarding the utility of immunosuppression in either group.

Treatment implications

Our data suggest that the presence of septal thickening and normal LV dimensions in a patient with a fulminant presentation and severe hemodynamic compromise portends a high likelihood of ventricular recovery. Maximal medical support, including intravenous inotropic agents and placement of a temporary LV assist device, should be considered for these patients in order to provide time for potential recovery of LV function, as has been described in case reports (22,23). Given the high likelihood of ventricular recovery, early consideration of cardiac transplantation may be avoided in patients with fulminant myocarditis.

Conclusions

This study suggests that patients with fulminant myocarditis have an echocardiographic presentation that is distinct from that of patients with acute myocarditis. Additionally, patients with fulminant myocarditis are significantly more likely to recover LV function than are those with acute myocarditis. Echocardiography provides important prognostic information and may aid in the clinically relevant classification of patients with histologically proven myocarditis.