Temporal echocardiography findings in patients with fulminant myocarditis: beyond ejection fraction decline

Abstract

The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients. In this study, changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored. We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment. Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled. Conventional echocardiographic measurements were obtained, and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (>50%). Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified, and their changes with time were monitored in 14 FM patients. All patients had severely impaired cardiac function. Steep improvement in LVEF and GLS were observed within 6 days. Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal. In conclusion, FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days. The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.

Keywords

fulminant myocarditis / acute myocarditis / 2D speckle tracking echocardiography / left ventricular function / global longitudinal strain

Introduction

Although myocarditis has been histologically and histochemically defined as an inflammatory disease of myocardial cells [¹,²], fulminant myocarditis (FM) is actually a clinical syndrome characterized by a flu-like prodrome, the rapid onset of severe hemodynamic compromise, and a severely impaired left ventricular (LV) function [³]. Prognosis in FM is poor. In-hospital survival rates are between 46% and 58% [⁴,⁵], but a group from Japan recently reported a higher survival rate (83.3%) [⁶]. Although no specific therapies have been established to improve prognosis for FM [⁷,⁸], the need for rapid therapeutic interventions is emphasized in the first few weeks of this disease. LV dysfunction usually normalizes in patients who have survived the acute period of illness [⁹,¹⁰]. Our hospital have reported an even lower in-hospital mortality (3.7%) after the application of “Life-Support-Based Comprehensive Treatment Regimen” (LSBCTR) [¹¹], but changes in LV function in the early stage of FM are not known.

Endomyocardial biopsy remains the gold standard for diagnosing suspected myocarditis; it uses the Dallas criteria extended by the histochemical proof of viral infection [²]. However, this procedure is rarely performed on FM because of its inherent procedural risk in patients with severely unstable hemodynamic status [¹²]. Cardiovascular magnetic resonance (CMR) has been used as a noninvasive imaging tool to underpin the diagnosis of acute myocarditis (AM) by demonstrating typical myocardial lesions, in which edema and late gadolinium enhancement (LGE) were utilized according to the Lake Louise criteria [¹³]. Owing to the diagnostic accuracy of CMR and in agreement with the current consensus, elevated necrosis biomarkers and CMR imaging can be combined for the diagnosis of FM [⁷]. CMR is often unavailable on an emergency basis.

Conventional 2D echocardiography can easily be performed in the bed and repeated as needed. Promising algorithms for evaluating LV deformation have been introduced by 2D speckle tracking echocardiography (2D STE). Strain parameters are useful in quantitatively assessing heart function and offer better sensitivity than conventional echocardiography for the detection of subclinical LV dysfunction in myocardial ischemia and diabetes [¹⁴,¹⁵]. Furthermore, myocardial strains and layer-specific quantification of myocardial strains are useful in diagnosing AM [¹⁶,¹⁷]. However, the value of strain echocardiography in FM has not been studied.

The main objective of our study was to assess the functional changes in LV by 2D STE in patients with FM clinically diagnosed according to typical clinical characteristics and elevated necrosis biomarkers and through CMR imaging. The distinct value of this study was that the following serial echocardiographic images were obtained during the hospitalization course of FM: LV structure, function, global/regional peak systolic longitudinal strains (GLS/RLS), and layer-specific longitudinal myocardial strains. Therefore, changes in LV function at the very early stages of FM can be assessed accurately after comprehensive therapeutic intervention [¹⁸−²¹].

Materials and methods

Study population

Tongji Hospital is one of the most important AM and FM center in China, and most FM patients in the Huazhong region (central China) are admitted in the hospital. A total of 95 patients clinically diagnosed with AM from June 30, 2017 to August 30, 2018 were prospectively screened according to method of Sagar et al. [¹]. Of these patients, 21 were diagnosed with FM, and one of them died. The remaining 20 patients were enrolled in the present study after satisfying the following inclusion criteria [⁹,²²]: (1) having rapid onset of symptoms of acute heart failure within less than two days; (2) having severe hemodynamic compromise that required high doses of vasopressors (≥5 μg/kg/min of dopamine or dobutamine); (3) mechanical life supports, such as intra-aortic balloon pumps (IABPs) and/or venoarterial extracorporeal membrane oxygenation (ECMO), were used in the early phase (day 1 or 2 of admission); and (4) CMR was performed before discharge and evidence of myocarditis was present. Only patients with CMR-confirmed myocarditis were enrolled. Coronary angiography was performed on patients older than 25 years to rule out acute myocardial infarction. The other exclusion criteria were severe valvular diseases, age below 15 years, and previous heart disease history. The flow diagram describing the selection of patients with FM is shown in Supplemental Fig. S1.

All the 21 patients received LSBCTR, which consists of (1) mechanical life support (positive pressure respiration, IABP with or without ECMO), (2) immunomodulation therapy using sufficient doses of glucocorticoids and immunoglobulins, and (3) application of neuraminidase inhibitors [¹⁸−²¹]. Five of the patients used ECMO.

Conventional echocardiographic examination

Sequential transthoracic echocardiography (TTE) scans were obtained from 20 patients (Supplementary Fig. S1). Then TTE scans were obtained at a frequency of 1 scan per day from admission until the day of LV ejection fraction (EF) recovery (>50%) before discharge. A Vivid E9 ultrasound scanner (GE Vingmed; Horten, Norway) was used. The measurements of systolic and diastolic interventricular septum thickness (IVS), LV posterior wall thickness (LVPW), LV end-diastolic dimension (LVEDD), end-systolic dimension (LVESD), fractional shortening (FS), and left atrial (LA) dimension (end-systole) were obtained from the parasternal long-axis view. LVEF, LV end-diastolic volume (LVEDV), and end-systolic volume (LVESV) were calculated by modified biplane Simpson method. Mitral E and A wave velocities were measured, and pulsed-wave tissue Doppler image tracing at the septal mitral annulus were conducted in the apical 4-chamber view for E′ velocity. E/A and E/E′ ratios were then calculated.

Two-dimensional speckle tracking echocardiography

Fourteen of the twenty patients were enrolled for the strain analysis. Six patients were excluded because of their poor echocardiography images and/or because of the presence of arrhythmias that interfered with image analysis (Supplementary Fig. S1). In TTEs, the 2D gray scale images of three consecutive cardiac cycles for each of the three apical views were saved for strain analysis. An experienced investigator blinded to the patients’ clinical information conducted the strain analysis offline and used EchoPAC (GE Vingmed; Horten, Norway). The measurements of longitudinal strains from non-multilayer analysis and from subendocardial and subepicardial myocardium were obtained as described previously [¹⁶]. Segmental peak systolic longitudinal strain (PSLS) values were averaged to achieve global GLS and segmental PSLS (basal, midsegment, or apical) was defined as the average of the PSLS values of the corresponding six segments (five segments for the apex) [¹⁵] on the basis of the AHA 17-segment LV model (Supplementary Fig. S2).

CMR acquisition and analysis

CMR was performed in all patients before their discharge when their statuses were stable. All CMR studies were analyzed with blinding to clinical and echocardiographic information. The patients were scanned with a 3T MR scanner (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). A survey scan was performed to localize the heart and diaphragm as previously described [¹⁶]. LGE imaging was performed in the horizontal long, vertical long, and short axes. An example of myocardial edema and necrosis in CMR is shown in Fig. 1.

Statistical analysis

Data were expressed as mean±SD for continuous variables or numbers (percentages) for categorical variables. Continuous variables between groups were analyzed by Student t-test or Mann–Whitney U test according to distribution. For paired comparisons, paired t-test or paired sample Wilcoxon rank test were performed for continuous variables, depending on the normality of the variables. The changes in EF or GLS from the first day to the sixth day of hospitalization were compared with repeated measure ANOVA.

For the investigation of inter- and intrapersonal measurement reproducibility, measurements were performed offline by two independent investigators. The intraclass correlation coefficients (ICC) were calculated. All analysis was performed with SPSS version 19.0 (SPSS, Inc., Chicago, IL, USA). Statistical tests were two-tailed and a P value of less than 0.05 was considered statistically significant.

Results

Patients’ baseline characteristics

Twenty-one patients were diagnosed as FM, of whom one patient died and 20 patients were enrolled in the study. The clinical characteristics of the patients on admission are shown in Table 1. The mean age was 34±18 years. All patients presented with a flu-like prodrome preceding the onset of cardiac symptoms in 1 week. Systolic blood pressure was 91±11 mmHg, and the heart rate was 100±23 bpm. The peak values of troponin I and NT-proBNP were greatly elevated (28 864.7±17 372.9 pg/mL and 17 019.2±16 796.4 pg/mL, respectively). IABP was applied to all patients in the first or second day of admission, and ECMO was performed in five patients. The average hospitalization period was 12±4 days. Virus were tested in FM patients. One fifth of the patients had Coxsackie virus B. Others types of viruses are provided in Supplementary Table S1.

Cardiovascular magnetic resonance

The diagnosis of myocarditis was confirmed by the typical clinical characteristics of patients, elevated necrosis biomarkers, and CMR findings. CMR was feasible in the acute phase of FM, and all the patients enrolled in the present study underwent MR scanning later at a median of 9 days after admission. The myocardium edema (T2WI) and necrosis (LGE) were observed in all patients. As shown in Fig. 1, a diffuse LGE pattern was observed frequently in patients with FM (Fig. 1).

Conventional echocardiographic data

Conventional echocardiographic measurements on admission and hospital discharge and their comparison are shown in Table 2. Briefly, LV chamber size was in normal range, and the wall thickness of IVS and LVPW in diastole was slightly increased upon admission, and they had no significant changes on discharge. All the patients had severely impaired LVEF on admission and showed great improvement before hospital discharge (EF: 30%±12% vs. 59%±7%; FS: 15%±6% vs. 32%±6%; P<0.001). With the recovery of LVEF and FS, the E/E′ ratio reduced significantly on hospital discharge compared with that on admission (11.22±3.46 vs. 18.74±11.6, P<0.01). These findings indicated that the severely damaged LV systolic and diastolic function is improved significantly on hospital discharge.

Strain analysis

The GLS was markedly reduced on admission and improved significantly before discharge (-8.45%±3.83% to −16.95%±1.85%, P<0.001). Similar to the GLS, apical PSLS, mid-PSLS, basal PSLS all presented great improvement upon hospital discharge (Table 3).

Regional strain changes between admission and hospital discharge was displayed in Fig. 2. Representative serial images in the bull’s-eye display in Fig. 2B showed the distribution of and changes in regional strains during hospitalization. Upon admission, the significantly reduced longitudinal strains were present in all regions, and pronounced reduction was observed in most segments (Fig. 2A). Upon discharge, all the regional strains improved significantly in comparison with the baseline level. However, the levels of improvement in the strains varied, and greater improvement was observed in the anteroseptal, septal, and inferior regions. The global longitudinal strain demonstrated great improvement, and different levels of improvement were observed in the regional strains.

Changes in LV EF and GLS with time at the acute phase of FM

For the assessment of the efficacy of LSBCTR in the treatment of FM at the acute phase, the variations in the trends of LVEF and GLS over time was analyzed in 14 patients (Fig. 3).

On day 3, LVEF and GLS demonstrated significant improvement compared with the data taken on day 1. Notably, the steep improvement in LVEF occurred in the early period. LVEF increased to>50% 6 days after admission (LVEF: 51%±11%). Compared with EF, the reduction of GLS was more severe, and improvement of GLS was slower in FM patients. The data indicated that the FM patients had severely impaired ventricular function upon admission but showed ventricular function recovery quickly after treatment.

Layer-specific strain analysis

The layer-specific quantification of myocardial deformation was analyzed upon admission and hospital discharge. The data is summarized in Fig. 4A, and representative images are shown in Fig. 4B. At the baseline, the GLS between the two layers markedly decreased. The absolute GLS value in the epicardium (-6.23%±2.42%) was lower than the endocardium (−8.72%±3.54%). Although the difference between the values did not reach statistical significance.

Upon hospital discharge, the layer strains apparently improved compared with the baseline level upon admission. The absolute GLS value was still lower in the epicardium than in the endocardium (-14.1%±1.76% vs. -19.62%±1.37%). However, there was no statistical significance between the changes of the epicardium and the endocardium.

Reproducibility of strain measures

ICC was 0.90 (95% CI 0.85–0.93) for inter-observer agreement and 0.94 (95% CI 0.90–0.97) for intra-observer agreement on strain measures. These results demonstrated that the deformational measures had good intra-observer and inter-observer correlation.

Discussion

Our study represented a detailed profiling of global, regional, and layer-specific myocardial deformation by 2D STE in FM patients. To the best of our knowledge, this is the first study to evaluate myocardial deformation changes in patients with FM. Moreover, changes in LV structure, function, and myocardial strains during the acute period of FM were monitored, and were of great value to the assessment of treatment efficacy. Our data demonstrated the effectiveness of the early application of LSBCTR, including mechanical life supports.

The most important finding in our study is the early and steep improvement in LV function at the super-acute phase of FM after our treatment. Previous studies have shown severely damaged myocardial function in patients with FM [¹⁰,²³]. In the present study, we found a significantly reduced LV function in FM patients upon admission, with average lowest EF at 30%±12% and FS at 15%±6%. Furthermore, patients with FM exhibits substantial recovery of LV function after the sixth month of follow-up [¹⁰]. However, whether functional recovery occurs earlier is impossible to determine if therapeutic interventions, such as mechanical life supports, are removed. In our study, the changes in LVEF and myocardial strains were monitored frequently. We observed the normalization or near normalization of LVEF and GLS in FM patients who have survived the acute phase in an extremely short period, approximately 6 days, which is a time window that is significantly shorter than that reported before. Notably, the super-acute phase of FM showed great improvement, indicating that the early days are likely the key period for the management of FM.

The strain echocardiography could provide additional information about the degree of cardiac involvement in patients with suspected AM [¹⁶,²⁴]. However, the value of myocardial deformation imaging in FM was not known. First, we demonstrated that the GLS were significantly decreased on admission at -8.45%±3.83%, a level much lower than the value reported in AM (-16.2%±3.6%) [¹⁶]. Significantly reduced GLS implies the severity of myocardial affection and supports the diagnosis of FM. Second, patchy and regional distribution of reduced regional wall motion abnormalities with no segmental difference were also observed in the FM. The abnormalities have been reported mainly in coronary artery disease and myocardial infarction. In the present study, the following characteristic features of regional strains were found in FM: (1) segmental wall motion abnormalities; (2) the patchy and diffused distribution of reduced strains across all segments; (3) nearly all region were greatly improved upon discharge. These data suggest that patchy and diffused distribution with no preferential alteration are the characteristics of regional deformations in patients with FM and may be due to diffused inflammation and myocardial edema [²⁵,²⁶].

Our study was also the first to evaluate layer-specific longitudinal systolic strain analysis in the acute phase of FM. According to the CMR findings, the involvement of myocardium in myocarditis was predominantly reported in the epicardial layer [²⁷,²⁸]. Our study demonstrated that the strains in FM upon admission were not significantly different from those upon discharge in terms of myocardium layer, although the absolute strain value is lower in epicardium than endocardium. Our findings are different from reports on non-FM myocarditis [¹⁶,¹⁷]. Myocardial impairment is severe, and GLS reduction is equal through the endocardium to epicardium. The recovery of strains over time is also identical among layers. Severely but equally impaired strain among different layers of myocardium may provide additional information on the diagnosis of FM.

Finally, no established therapies on FM are currently available, several trials on the role of immune-suppressive therapy have been tested, and IVIg treatment in FM [²⁹–³²]. Most data suggested the beneficial role of IVIg treatment in biopsy-proven viral myocarditis [²⁹–³¹] and benefit from immune-suppressive therapy in biopsy-proven autoreactive myocarditis [³¹,³²]. Other reports suggested the positive value of life assist devices, such as IABP and ECMO, in FM [⁸,³³]. IABP can reduce LV afterload. ECMO mainly provides circulatory supports while increasing the afterload that may worsen pulmonary edema. In the present study, LSBCTR [¹⁸,¹⁹] was used in the management of FM. IABPs were applied to patients who used ECMO to reduce the afterload. Our study had surprisingly 4.8% in-hospital death rate (20 patients survived and 1 patient died in all 21 patients) that was much lower than 46% as reported by others [⁴,⁷]. We proposed that the early phase is the key period in the management of FM and the early initiation of LSBCTR including mechanical life supports is essential to the survival of FM patients. Further studies are needed to identify appropriate candidates and when is the best time to initiate mechanical supports.

Study limitations

Our study was conducted in a single center, and the patients enrolled were relatively small. Secondly, patients with FM were critically ill and hemodynamically unstable at presentation, and invasive myocardium biopsy was not performed in our study. However, FM was diagnosed in our study through method combining elevated necrosis biomarkers and CMR imaging. Thirdly, patients with high degree of heart block or irregular rhythm were excluded from the study in the strain analysis which could cause selective bias.

Conclusions

Our study found that the FM patients exhibited a steep improvement in ventricular function within a short period of time after onset of symptoms. We suggested that the early application of mechanical life supports likely play a pivotal role in the recovery. The patchy and diffused distribution of reduced RLS was observed in the myocardium in FM. The impairment of strain through endocardium and epicardium was equal. The 2D STE analysis was more informative than conventional echocardiographic parameters in assessing the mechanics of LV function in FM and assisting in diagnosing FM.

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