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Endomyocardial Fibrosis
Introduction
Endomyocardial fibrosis is a rare condition in North America but is prevalent in tropical and subtropical regions of the developing world, where it is often referred to as tropical endomyocardial fibrosis. Marked by fibrous deposits in the endomyocardium of the right and left ventricles, the disease leads to restrictive cardiomyopathy.[1] Endomyocardial fibrosis is endemic in parts of Africa, where it was first reported in the 1940s, and is the etiology of up to 20% of cases of heart failure.[2] Endomyocardial fibrosis is also common in rural regions of Asia and Latin America. Although the precise cause remains unclear, environmental factors and infections are believed to trigger chronic inflammation and fibrosis of the endomyocardium.
Because the pathology of endomyocardial fibrosis is similar to eosinophilic cardiomyopathy and hypereosinophilic syndromes, it is sometimes considered part of a broader disease spectrum that includes Löffler endocarditis.[3][4][5] The natural history of endomyocardial fibrosis is characterized by an active inflammatory phase, which typically causes nonspecific symptoms, followed by chronic inflammation and fibrous deposits in the heart, eventually resulting in restrictive cardiomyopathy. Clinical manifestations of endomyocardial fibrosis include heart failure, arrhythmias, and systemic thromboembolism. Without treatment, the prognosis of endomyocardial fibrosis is poor.[6]
Etiology
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Etiology
Endomyocardial fibrosis is a multifactorial disorder with an incompletely understood etiology. Studies suggest the involvement of various potential causes and contributing factors, including:
- Environmental and infectious factors
- Endomyocardial fibrosis is often linked to parasitic infections, particularly schistosomiasis. In endemic regions, Schistosoma species are associated with endomyocardial fibrosis development due to the parasite-triggered inflammatory response that can lead to fibrotic changes in the heart.[7][8][9] While evidence suggests viral infections might play a role, this connection is less clear.
- Chronic exposure to environmental toxins or pollutants is another potential contributor, though not as well-documented.[10] Additionally, some speculate that herbal preparations may play a role in the pathogenesis of endomyocardial fibrosis, though this remains unproven.[11]
- Nutritional deficiencies
- Nutritional deficiencies have been implicated in endomyocardial fibrosis development, especially protein, magnesium, and trace element deficiencies.[12][13] Poor nutrition, particularly in developing regions, can contribute to the disease's onset. Broader nutritional deficiencies, often seen in impoverished areas, may exacerbate or contribute to the development of the disease by affecting overall heart health and immune function.[14]
- Genetic and hereditary factors
- Although endomyocardial fibrosis is not known to be a genetic disorder, some evidence suggests a possible genetic predisposition.[15][16] Individuals in certain populations may be more susceptible due to inherited traits that influence the disease's development. In some cases, a family history of endomyocardial fibrosis or related conditions may suggest a hereditary component, although this is less well-established compared to other causes.[17][18]
- Autoimmune reactions
- Some evidence suggests that autoimmune mechanisms might contribute to endomyocardial fibrosis. Inflammatory processes driven by immune system dysfunction could lead to fibrotic changes in the myocardium. The immune-mediated inflammatory response is suggested by the high levels of immunoglobulins in patients with endomyocardial fibrosis.[19] Some study results have also revealed autoantibodies against myocardial proteins in endemic areas, which further suggests the possible role of autoimmune reactions in the pathogenesis of this disease.[20][21]
- Socioeconomic and lifestyle factors
- Lower socioeconomic status often correlates with higher rates of endomyocardial fibrosis, likely due to associated factors such as limited access to healthcare, poor nutrition, and higher prevalence of infectious diseases.[22] Poor living conditions and inadequate medical care in certain regions can exacerbate the risk of developing endomyocardial fibrosis, particularly where preventive measures and treatments for underlying conditions are lacking. Recent changes in the prevalence of endomyocardial fibrosis in some endemic areas further support the role of socioeconomic status in the etiology of endomyocardial fibrosis.[23]
In summary, the etiology of endomyocardial fibrosis appears multifactorial and involves environmental, infectious, nutritional, genetic, and socioeconomic factors. Understanding these elements is crucial for preventing, diagnosing, and treating the disease.
Epidemiology
Although there is limited data on the epidemiology of endomyocardial fibrosis, it is estimated to be the most common cause of restrictive cardiomyopathy, especially in tropical and subtropical areas of the world.[24]
Geographical Distribution
The high-prevalence regions for endomyocardial fibrosis include Africa, Asia, and South America. In sub-Saharan Africa, endomyocardial fibrosis is mainly reported in Uganda, the coastal region of Mozambique, and some areas of West Africa. Rare cases have also been reported in Congo and Malawi.[25][26][27] In India, endomyocardial fibrosis has been reported in the coastal areas of Kerala state. China has also reported a significant number of cases in the Guangxi province.[28][29] Brazil and Colombia are the main countries where EMF cases have been documented in South America.[30]
Demographics
Endomyocardial fibrosis can affect individuals of any age but is most commonly diagnosed in children and young adults of poor socioeconomic status.[31] Although endomyocardial fibrosis affects individuals of any sex, some studies have reported a high prevalence in women of childbearing age, and the reasons for this gender disparity are not fully understood.[25]
Risk Factors
Certain populations, including those living in poor socioeconomic conditions, are at higher risk, which might correlate with nutritional deficiencies or environmental factors. Study results have also suggested that endomyocardial fibrosis may be linked to parasitic infections such as schistosomiasis, which are more common in endemic areas.[1]
Pathophysiology
The pathophysiology of endomyocardial fibrosis involves a complex interplay of inflammation, fibrotic tissue deposition, and impaired cardiac function. The excessive fibrosis of the endocardium and myocardium leads to restricted cardiac filling, heart failure, and associated complications.
Inflammation and Immune Response
In endomyocardial fibrosis, chronic inflammation often precedes the fibrotic changes in the heart. In regions where schistosomiasis is endemic, parasitic infections can initiate this inflammation, leading to endocardial damage.[32] The immune response, particularly the release of cytokines and growth factors, promotes the development of fibrosis. This inflammatory environment sets the stage for cardiac tissue remodeling, ultimately contributing to the disease’s progression.[33]
Fibrosis and Scar Formation
Following the inflammatory response, fibroblasts activate, producing excessive collagen and extracellular matrix proteins and forming fibrous tissue.[34] The accumulation of collagen disrupts the normal cardiac architecture and function.[35] Endomyocardial fibrosis affects both ventricles in 50% of cases, while 40% involve only the left ventricle and 10% involve only the right. The hallmark of endomyocardial fibrosis is fibrotic obliteration of the ventricle, characterized by focal or diffuse thickening of the endocardium, which impairs normal cardiac function. Fibrosis typically involves the apices of the ventricles, extending from the apex to the posterior mitral leaflet in the left ventricle and sparing the anterior leaflet and left ventricular outflow tract. Fibrosis may extend to the papillary muscles and chordae tendineae, leading to atrioventricular valve distortion and regurgitation.[31] In advanced stages, endocardial calcific deposits and thrombus formation can occur. This process does not involve the epicardium, and coronary artery obstruction is very uncommon. There is no involvement of the extracardiac organs.[36][37]
Impaired Cardiac Function
Fibrotic changes from endomyocardial fibrosis result in restrictive cardiomyopathy, limiting the heart’s ability to expand and fill appropriately during diastole, reducing cardiac output, and elevating chamber pressures. Over time, patients develop symptoms of heart failure, including shortness of breath, fatigue, and edema, due to increased pulmonary and systemic venous pressures. In some cases, fibrosis can involve heart valves, leading to dysfunction and exacerbating hemodynamic issues and heart failure symptoms.[38] The presence of fibrous tissue also increases the risk of thrombus formation and thromboembolic events like stroke, while arrhythmias may further complicate the disease’s clinical presentation.
Histopathology
During pathological examination of advanced endomyocardial fibrosis, the ventricular cavities appear significantly reduced in size, while the atria are notably dilated. Histopathological analysis reveals hallmark endocardial thickening, which results from the increased number and abnormal activation of cardiac fibroblasts in the subendocardium, leading to excessive collagen production.[39]
Inflammatory infiltrates, specifically lymphocytes, can be observed at the junction of the endocardium and myocardium. Additionally, interstitial fibrosis, intramyocardial inflammatory infiltrates, and scar tissue form near areas of subendocardial fibrosis. These lesions are believed to stem from ischemic injury related to microvascular alterations.[14]
History and Physical
Endomyocardial fibrosis typically presents in different phases, with clinical features depending on the cardiac chambers involved and the disease's severity. In the initial acute carditis phase, patients may exhibit a febrile illness and, in severe cases, cardiogenic shock. Differentiating the acute phase of endomyocardial fibrosis from other conditions, such as acute viral myocarditis or the acute phase of rheumatic fever, can be challenging.[38] Most patients, however, present during the chronic, burnt-out phase of the disease, which is marked by advanced complications, including heart failure, arrhythmias, or thromboembolic events.[27] Common physical signs in this chronic phase include nonspecific symptoms of chronic heart failure, along with specific features like periorbital edema, enlarged parotid glands, and proptosis.[1]
Clinical findings in patients with predominantly right ventricular involvement include ascites, hepatomegaly, lower extremity edema, elevated jugular venous pressure, and tricuspid regurgitation. Giant v waves and a rapid y descent during the jugular venous pulse examination are frequent.[40] Marked ascites with minimal peripheral edema may suggest biventricular involvement.[41]
Left ventricular involvement, on the other hand, manifests as predominant dyspnea, along with fatigue, cachexia, and orthopnea. Mitral regurgitation may occur due to fibrosis affecting the chordae tendineae and the posterior mitral valve leaflet. Pulmonary hypertension, along with the presence of an S3 or S4 gallop, is frequently noted in left ventricular endomyocardial fibrosis.[42]
Evaluation
Electrocardiogram
In advanced stages of endomyocardial fibrosis, low-voltage QRS complexes and nonspecific ST- and T-wave abnormalities are observed on a routine electrocardiogram (ECG). Also, atrioventricular blocks, intraventricular conduction delay, and right or left bundle branch blocks are frequently seen. Left atrial enlargement and atrial arrhythmias occur in advanced cases of left ventricular endomyocardial fibrosis.[43][44] The other nonspecific ECG features may include right ventricular enlargement, rightward frontal QRS axis, and nonspecific intraventricular conduction delays.
Chest Radiography
Cardiomegaly, ranging from mild to severe, along with atrial enlargement and pulmonary vascular congestion, can often be identified in patients with endomyocardial fibrosis. In some cases, endomyocardial calcification is visible. Additionally, pleural and pericardial effusions may occur, regardless of whether left or right ventricular involvement predominates, further contributing to the disease's complexity.[45]
Echocardiography
Echocardiography is the primary diagnostic tool for identifying classical presentations of endomyocardial fibrosis.[46] Diagnostic criteria are based on echocardiographic parameters, and endomyocardial fibrosis is confirmed when 2 major or 1 major and 2 minor criteria are met.[31] This modality helps assess the extent and severity of the disease by identifying key pathological features such as apical obliteration and endocardial surface thrombi. Microbubble contrast enhances imaging quality, allowing for better visualization of the left ventricular cavity, atrioventricular valve abnormalities, and restrictive filling patterns.
In right-sided endomyocardial fibrosis, obliteration of the trabecular aspect of the right ventricular cavity is noted.[47] With further disease advancement, the right ventricular cavity volume and worsening tricuspid regurgitation are reduced due to tricuspid annular dilatation. Spontaneous echo contrast and right atrial thrombi are also commonly observed. In left-sided endomyocardial fibrosis, ventricular apex obliteration leads to restricted movement and compensatory hypercontractility in the basal ventricle. Fibrosis affecting the posterior mitral valve leaflet causes severe eccentric mitral regurgitation, and both forms of EMF show atrial enlargement.[48] Doppler echocardiography reveals a restrictive filling pattern characterized by a short deceleration time, shortened isovolumetric relaxation time, and rapid early diastolic filling followed by minimal flow in late diastole. Reduced flow propagation velocity has also been documented in many patients.[49]
Cardiovascular Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (MRI), while relatively expensive and not widely accessible, proves valuable for early diagnosis of endomyocardial fibrosis by detecting subendocardial fibrosis with late gadolinium enhancement, often preceding cavity obliteration and restrictive filling patterns.[50] More sensitive than echocardiography in detecting intracardiac thrombi, cardiac MRI is critical in monitoring treatment response and assisting in preoperative assessments.[51][52] By offering detailed tissue characterization, cardiac MRI has been shown to improve early detection of endomyocardial fibrosis, facilitating timely intervention to improve patient outcomes.[50]
Cardiac Hemodynamics
Cardiac catheterization and invasive hemodynamic assessment are rarely required to evaluate endomyocardial fibrosis in the era of noninvasive imaging. The characteristic findings include a dip-and-plateau pattern consistent with restrictive ventricular filling. Elevated left ventricular end-diastolic pressure is also commonly observed. Left ventricular angiography reveals characteristic obliteration of the apex of the involved ventricle.[48]
Laboratory
There are no definitive laboratory tests for endomyocardial fibrosis. However, eosinophilia often appears alongside elevated nonspecific acute-phase reactants during the acute inflammatory stage. In the chronic phase, hypoalbuminemia is frequently noted due to protein-losing enteropathy, though this too lacks specificity.[1] Cardiac biomarkers such as elevated troponins or B-type natriuretic peptides signal myocardial damage and heart failure. Inflammatory markers like C-reactive protein help unveil the ongoing inflammatory processes. Careful tracking of electrolytes and renal function is vital, especially when managing heart failure and tailoring medication strategies to individual needs.
Treatment / Management
Medical Management
Medical management of endomyocardial fibrosis is highly challenging, with one-third to one-half of patients with advanced disease dying within 2 years of diagnosis. Atrial fibrillation is associated with a poor prognosis, though rate control strategies may provide symptomatic relief.[53] Immunosuppressive therapies have limited benefit since most patients present after the myocarditis phase has ended.[30] Symptom management is primarily via diuretic administration, and patients may benefit from angiotensin-converting enzyme (ACE) inhibitors and beta blockers. Anticoagulation is advised for those with thrombi identified on imaging. The role of defibrillators in preventing sudden cardiac death remains unclear, as device-based therapies may offer limited benefit due to the aggressive nature of the disease.
Surgical Management
Surgery can significantly improve survival in patients with advanced heart failure due to endomyocardial fibrosis, especially when performed in the right clinical setting.[54][55] The most common approach involves endocardectomy, often combined with valvular replacement when necessary.[56][57] However, expertise and surgical management options are limited in many endemic regions, and surgery carries a high mortality rate, reaching 15% to 20%.[58][59] Cavopulmonary connections may benefit patients with right ventricular involvement and a small right ventricular cavity. Although surgery has a high risk, early-stage endocardectomy remains the only option for improving outcomes.[60] Heart transplantation offers no established benefit for patients with advanced endomyocardial fibrosis.[1](B2)
Differential Diagnosis
The differential diagnosis of endomyocardial fibrosis includes, but is not limited to:
- Viral myocarditis
- Infiltrative cardiomyopathies, such as cardiac amyloidosis
- Inflammatory cardiomyopathies, such as cardiac sarcoidosis
- Inherited and idiopathic dilated cardiomyopathy
- Cardiac noncompaction and associated cardiomyopathy
- Carcinoid heart disease
- Anthracycline toxicity
- Constrictive pericarditis
- Radiation-induced cardiomyopathy
Prognosis
The long-term prognosis for advanced-stage endomyocardial fibrosis with medical treatment is quite unfavorable, with a 75% mortality rate within 2 years.[6] Overall, endomyocardial fibrosis contributes to approximately 20% of heart failure hospitalizations in Nigeria, Equatorial Guinea, and Uganda, making it the second most common cause of pediatric admissions for acquired heart disease in these regions, following rheumatic heart disease.[61][62]
Complications
Endomyocardial fibrosis leads to a range of complications due to progressive fibrotic changes in the heart, resulting in restrictive cardiomyopathy. Common complications include:
- Heart failure: The primary complication is restrictive cardiomyopathy, which impairs the heart's ability to fill properly during diastole and leads to chronic heart failure. This can manifest as right- or left-sided heart failure. As endomyocardial fibrosis is progressive, it can result in acute decompensated heart failure, cardiogenic shock, and recurrent hospitalizations.[38] Patients often experience worsening symptoms such as dyspnea, fatigue, and fluid retention, requiring frequent medical intervention.
- Arrhythmias: The fibrosis and scarring in the myocardium can disrupt the cardiac conduction pathways, leading to atrial fibrillation or other arrhythmias. Atrial fibrillation is particularly concerning as it worsens the prognosis and increases the risk of thromboembolic events. The altered electrical environment in the ventricles can also increase the risk of life-threatening ventricular arrhythmias and sudden cardiac death.[44][63]
- Thromboembolic events: The inflammatory milieu, endothelial dysfunction, and turbulent blood flow associated with fibrotic changes and impaired cardiac function significantly increase the risk of thrombus formation, particularly within the ventricles and dilated atria. If dislodged, these clots can lead to stroke, pulmonary thromboembolism, or other thromboembolic events, posing serious complications for affected patients.[64]
- Valvular dysfunction: Fibrosis can extend to the atrioventricular valves, leading to valvular dysfunction. The fibrotic involvement of the mitral or tricuspid valve apparatus, including the chordae tendineae, leads to atrioventricular valve regurgitation. This exacerbates heart failure symptoms and can further deteriorate cardiac function.[65]
- Pulmonary hypertension: Long-standing heart failure can lead to secondary pulmonary hypertension, which can further strain the heart and worsen respiratory symptoms.
- Infective endocarditis: Fibrotic tissue and valve abnormalities increase the susceptibility to infection of the endocardium and heart valves.
- Pericardial effusion: In some cases, pericardial effusion can occur, worsening the patient's hemodynamic status and contributing to symptoms of heart failure.
- Sudden cardiac death: Although less common, the combination of arrhythmias, thromboembolic events, and advanced heart failure can increase the risk of sudden cardiac death.
Deterrence and Patient Education
Effective patient education for endomyocardial fibrosis involves thoroughly understanding the condition, managing symptoms, adhering to treatment, making lifestyle modifications, and recognizing complications. Providing comprehensive information and support helps patients to better manage their condition and improve their overall quality of life.
Understanding the Condition
Explain that endomyocardial fibrosis is restrictive cardiomyopathy where fibrous tissue accumulates in the heart, making it difficult to expand and fill with blood; this leads to heart failure and other complications. Discuss potential causes such as parasitic infections (eg, schistosomiasis), nutritional deficiencies, and other contributing factors. Emphasize that the exact cause may vary from patient to patient.
Symptoms and Monitoring
Educate patients about common symptoms such as shortness of breath, fatigue, leg or abdominal swelling, and difficulty with physical activities. Encourage them to report any new or worsening symptoms promptly. Advise patients on the importance of regular follow-up visits and diagnostic tests to monitor disease progression and manage symptoms effectively. Advise on how to balance rest and activity to avoid overexertion. Tailor recommendations to the patient’s current heart function and physical capability level. Discuss strategies for managing the condition while traveling or at work, including any necessary precautions or adjustments.
Treatment and Management
Explain the purpose of prescribed medications, such as diuretics, antihypertensives, or antiarrhythmics, and stress the importance of taking them as directed. Recommend a heart-healthy diet low in salt and rich in fruits, vegetables, and whole grains to help manage fluid retention and overall health. Advise on safe physical activity levels and tailor exercise recommendations to the patient’s condition and tolerance. Encourage maintaining a healthy weight to reduce the strain on the heart. Educate patients on avoiding situations or substances that can exacerbate their condition, such as excessive alcohol, smoking, or high-salt foods. Stress the need for regular check-ups to monitor the condition, adjust treatments, and address emerging issues. Inform patients about the types of tests they may need, such as echocardiograms or blood tests, and their importance in managing EMF.
Complications and Emergency Signs
Inform patients about potential complications, including arrhythmias, thromboembolism, and worsening heart failure. Explain the signs of these complications and when to seek emergency care. Guide what to do in case of sudden or severe symptoms, such as shortness of breath, chest pain, or signs of a stroke.
Psychological and Emotional Support
Acknowledge the emotional impact of living with a chronic condition and offer support resources such as counseling or support groups. Encourage stress-reducing activities and techniques to help manage the psychological burden of the illness. If applicable, educate family members and caregivers about EMF, its management, and how they can support the patient. Encourage open communication between patients, caregivers, and healthcare providers to ensure comprehensive care and support.
Enhancing Healthcare Team Outcomes
Effective endomyocardial fibrosis management requires a multidisciplinary approach involving clinicians nurses, pharmacists, and other health professionals. Clinicians and advanced clinicians must have strong diagnostic skills to recognize the unique clinical features and implement appropriate treatment strategies. Nurses are critical in monitoring patients' symptoms, administering medications, and educating on disease management. Pharmacists ensure the safe and effective use of medications, including anticoagulants and heart failure therapies, while also addressing potential drug interactions. Integrating these professionals fosters comprehensive care that improves patient outcomes and enhances safety.
Interprofessional communication and care coordination are essential for optimizing team performance in treating patients. Effective communication ensures that all team members know the patient's clinical status and care plan, enabling timely interventions and reducing the risk of complications. Collaboration across disciplines allows for a patient-centered approach, with individualized care plans addressing medical and psychosocial needs. Coordinated follow-up care, including regular monitoring for heart failure progression and thromboembolic risks, helps reduce hospital readmissions and improve long-term outcomes. Through seamless teamwork, the healthcare team can provide high-quality care that enhances safety and optimizes outcomes for patients with this rare disease.
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<p>Contributed by Intisar Ahmed</p>
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