Graphical abstract
Highlights
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EMF is frequently detected at a late stage when symptoms of heart failure manifest.
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CMR is a robust tool for the noninvasive assessment of EMF.
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Multimodality imaging helps detect early stages and monitor disease progression.
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Occurrences beyond tropical regions suggest multifactorial pathogenesis.
Introduction
Endomyocardial fibrosis (EMF) is a rare cardiac disease known to cause restrictive cardiomyopathy. It is characterized by fibrosis of the endocardium and fibrotic obliteration of the ventricular cavity, with a hemodynamic consequence of diastolic dysfunction and heart failure.1 The exact cause of EMF is unknown, and it may mimic other cardiac diseases such as Ebstein anomaly and arrhythmogenic cardiomyopathy.
Transthoracic echocardiography (TTE) usually suggests the initial suspicion of this disease and is associated with classical findings, but the utility of multimodality imaging is often necessary for the final diagnosis. We describe a young woman residing in a large metropolis of southeast Asia who presented with features of restrictive cardiomyopathy following a diagnosis of chronic myeloid leukemia (CML) who was found to have EMF. The report emphasizes the importance of multimodality imaging in the diagnosis of EMF.
Case Presentation
An 18-year-old woman presented to our tertiary care center with complaints of fever and weight loss. The patient also reported generalized fatigue and night sweats. Medical history was insignificant. There was no history of substance use disorder and no family history of hematological diseases.
On initial investigation, a complete blood count revealed a hemoglobin of 9.6/dL, hematocrit of 31%, mean corpuscular volume of 70 FL, mean corpuscular hemoglobin of 20 picogram, white blood cell count of 45 ∗ 10E9/L, neutrophils 62%, lymphocytes 1%, eosinophils 1%, promyelocytes 9%, myelocytes 13%, metamyelocytes 10%, blast cells 3%, and platelet count of 352 ∗ 10E9/L. The peripheral blood smear revealed a leukoerythroblastic blood film. A bone marrow biopsy was performed, which was suggestive of CML. The bone marrow chromosomal analysis revealed a translocation of 9q34 and 22q11.2, suggestive of the Philadelphia chromosome.
Two years after the diagnosis of CML, the patient presented to the general cardiology clinic with complaints of exertional dyspnea and abdominal distension. On examination, blood pressure was 93/62 mm Hg, and heart rate was 82 beats per minute. Ascites and bilateral pitting edema were present, and jugular venous pressure was raised. A TTE was performed for evaluation of cardiac structure and function, as discussed below.
The parasternal long-axis view showed a dilated right ventricle (RV; Video 1) and mild mitral regurgitation from a mildly thickened valve. There was no aortic regurgitation, pulmonary, tricuspid, or aortic stenosis. The left ventricular (LV) ejection fraction was estimated to be 60% based on visual assessment. The parasternal short-axis view at the level of the aortic valve showed an intact interatrial septum. The right ventricular (RV) inflow view revealed a dilated tricuspid annulus with tricuspid regurgitation (TR; Video 2). The continuous-wave Doppler across the tricuspid valve was dense, early peaking, and triangular, suggestive of severe TR, with peak pressure gradients of 9 mm Hg (Figure 1). The TR was graded as severe based on structural abnormality (dilated annulus) and the dense early peaking triangular continuous-wave Doppler. On the apical 4-chamber view, there was a complete obliteration of the RV apex and to some extent of the left ventricle (LV). Additionally, there was biatrial enlargement (Video 3). The mitral inflow pulsed-wave Doppler was suggestive of a restrictive filling pattern (E/A > 2; Figure 2). The overall echocardiographic findings were suspicious for EMF.
Figure 1.
Right ventricular inflow view with continuous-wave Doppler across the tricuspid valve demonstrates a dense, early peaking, and triangular signal (arrow) suggestive of severe TR. Peak pressure gradients of 9 mm Hg.
Figure 2.
Two-dimensional TTE, apical 4-chamber view. Pulsed-wave and tissue Doppler demonstrates the septal e’ is reduced, mitral inflow E/A ratio is >2.0, E/e' ratio is ∼ 20, and the E-wave deceleration time is <160 msec (restrictive filling pattern).
With an initial suspicion of EMF, the patient was referred for cardiovascular magnetic resonance (CMR) imaging for further tissue characterization. Cardiovascular magnetic resonance imaging was performed with a 1.5 Tesla scanner. Morphologically, the left atrium (LA) was mildly dilated, whereas the right atrium (RA) was severely dilated. The RV and LV volumes were diminished with the obliteration of the apices (Video 4). The LV end-diastolic volume (77 mL), end-systolic volume (23 mL), and mass (60 g) as well as the RV end-diastolic volume (73 mL) and end-systolic volume (44 mL) were small. The RV ejection fraction was reduced (39%). There was mild to moderate mitral regurgitation and severe TR. The fat suppression sequence identified no abnormality. The early gadolinium-enhanced imaging revealed extensively layered thrombi in the LV and RV apices (Figure 3). The late gadolinium-enhanced (LGE) sequence revealed extensive endocardial enhancement in both ventricles (in the RV more than in the LV; Figure 4). The overall CMR diagnosis was consistent with EMF.
Figure 3.
Cardiovascular magnetic resonance imaging, apical 4-chamber (left) and apical 2-chamber (right) views, early gadolinium-enhanced sequence, demonstrates an extensively layered thrombus at both the LV (yellow arrow) and RV apex (red arrow).
Figure 4.
Cardiovascular magnetic resonance imaging, apical 3-chamber (top left), apical 4-chamber (top right), apical 2-chamber (bottom left), and midventricular short-axis (bottom right) views, LGE sequence, demonstrates extensive endocardial enhancement in both ventricles, but in the RV more than in the LV (arrows).
The patient demonstrated clinical improvement with diuretic therapy and is being followed regularly in the outpatient heart failure clinic.
Discussion
Endomyocardial fibrosis is known to be a disease of poverty and tropical regions. While the exact cause remains unknown, several etiologies have been defined in the literature. It is closely related to Loeffler’s endocarditis, which occurs in the setting of peripheral eosinophilia. The global distribution of published cases is centered around countries in sub-Saharan Africa, particularly Uganda. However, more cases are being identified in Kerala, a north Indian state. It has also been linked to a diet low in protein, particularly increased cassava ingestion.2 The study also suggests a geochemical hypothesis, with an increased burden of cases of EMF in areas with high monazite density.2
The occurrence of EMF in a patient with CML may be coincidental and does not establish a cause-effect relationship. More commonly, EMF has been associated with several socioenvironmental factors such as malnutrition, helminthic infections, nutritional deficiency, and poverty. There is only limited evidence that CML is associated with EMF in the absence of eosinophilia. An association between CML and EMF has been described previously in a young man with BCR-ABL-negative CML who presented with signs and symptoms of right-sided heart failure and was found to have isolated RV EMF on subsequent evaluation.3
The initial acute stage presents in 1 to 2 months’ duration as acute febrile illness and endomyocardial inflammation and necrosis. Only in severe cases do patients present with cardiogenic shock and heart failure. This is followed by a subacute thrombotic stage (10 months) characterized by endothelial damage, formation of thrombus, and restriction of valve motion. In the fibrotic stage (1-2 years), there is a fibrotic replacement of thrombi with an end stage of restrictive cardiomyopathy and valve incompetence.4 The disease is frequently detected at a late stage when symptoms of heart failure, particularly RV failure, manifest.5 The classical imaging findings described are also observed in subacute and chronic stages, as demonstrated in our patient.
Although it is a rare disease, one may encounter such cases in clinical imaging practice. Recognition of classical echocardiographic patterns and the utility of multimodality imaging in an appropriate clinical context helps with the correct diagnosis. Echocardiograms are usually unremarkable in the initial acute stage. However, the presence of a thrombus in the absence of an akinetic apex can be the first clue of the disease. The classical “kissing ventricle” appearance on the TTE can be confused with the apical variant of hypertrophic cardiomyopathy (HCM). By adjusting the gain and focusing on the apex, an increased echogenicity is suggestive of fibrotic endocardium. The degree of involvement can range from isolated apex to subvalvular structures. A three-dimensional TTE provides further details on the disease pattern and extent. It can reveal progressive circumferential obliteration of the LV cavity as one sees from base to apex.1 The advantage of TTE includes availability and ease of repeating the study for assessing response to the treatment. On a TTE, the presence of apical thrombi can be confused with apical HCM. Administration of an ultrasound-enhancing agent will increase the sensitivity for detecting ventricular thrombi in EMF and can be used to differentiate EMF from the apical HCM. In apical HCM, the LV apical lumen is visualized and appears as an ace of spades configuration during systole. However, in EMF, the layered apical thrombi appear as a persistent opacification defect.1
Cardiovascular magnetic resonance imaging has emerged as a robust tool for the noninvasive assessment of EMF: it offers anatomical and functional details with superior accuracy and resolution compared to TTE; helps differentiate EMF from other imaging mimickers; provides tissue characterization—including fibrosis, necrosis, and edema; defines viability; detects microthrombi; and helps in the accurate evaluation of RV function and volume. An added advantage is the detection of an earlier stage of the disease, which cannot be detected by other noninvasive modalities such as TTE.1 In patients with EMF/Loeffler’s endocarditis, the stage of the disease can be assessed as follows: the acute inflammatory stage is defined by the presence of myocardial edema on T2-weighted images, whereas the absence of edema suggests a chronic stage. Gadolinium-enhanced sequences can detect thrombi of variable sizes and define the thrombotic stage, whereas LGE defines the late stage. The characteristic LGE appearance of EMF is subendocardial hyperenhancement in a noncoronary artery, oversitting thrombi of variable ages. The extent of the scar bears prognostic implications.6
Conclusion
Endomyocardial fibrosis is rarely encountered in clinical practice. The utility of multimodality imaging in an appropriate clinical context can help differentiate EMF from other imaging mimickers. Multimodality imaging also helps define the stage and extent of the disease and provides prognostication. Serial imaging can help determine the response to the treatment.
Ethics Statement
The authors declare that the work described has been carried out by The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Ethical approval was also obtained from the ethical review committee of the hospital.
Consent Statement
The authors declare that informed consent was obtained for the usage of de-identified images and relevant investigations of the patient.
Funding Statement
The authors declare that this report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosure Statement
The authors report no conflict of interest.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.case.2023.12.001.
Supplementary Data
Two-dimensional TTE, parasternal long-axis view, demonstrates a small LV with normal LV ejection fraction, dilated LA, and dilated RV outflow tract (star).
Two-dimensional TTE, RV inflow view without (left) and with (right) color-flow Doppler, demonstrates a massively dilated RA with lack of coaptation of the tricuspid valve leaflets (arrow) and severe TR with laminar flow.
Two-dimensional TTE, apical 4-chamber view, demonstrates obliteration of the RV apex (yellow arrow) and to a lesser extent the LV apex (red arrow). There is severe biatrial enlargement.
Cardiovascular magnetic resonance imaging, apical 4-chamber view, steady-state free precession sequence, demonstrates the massively dilated RA, dilated LA, and small RV and LV with normal systolic function and obliteration of the apices (arrows).
References
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Associated Data
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Supplementary Materials
Two-dimensional TTE, parasternal long-axis view, demonstrates a small LV with normal LV ejection fraction, dilated LA, and dilated RV outflow tract (star).
Two-dimensional TTE, RV inflow view without (left) and with (right) color-flow Doppler, demonstrates a massively dilated RA with lack of coaptation of the tricuspid valve leaflets (arrow) and severe TR with laminar flow.
Two-dimensional TTE, apical 4-chamber view, demonstrates obliteration of the RV apex (yellow arrow) and to a lesser extent the LV apex (red arrow). There is severe biatrial enlargement.
Cardiovascular magnetic resonance imaging, apical 4-chamber view, steady-state free precession sequence, demonstrates the massively dilated RA, dilated LA, and small RV and LV with normal systolic function and obliteration of the apices (arrows).