Narrative review
How to recognize endomyocardial fibrosis? Ilaria Dato Endomyocardial fibrosis is a disease of unknown cause, characterized by the development of restrictive cardiomyopathy. Although it is endemic in Africa, some cases have been described in Asia, South America and Europe, where a substantial unfamiliarity with this disease still exists. Moreover, differential diagnosis of endomyocardial fibrosis with other cardiomyopathies can be difficult, especially in asymptomatic patients and in initial stage of the disease. After initial echocardiographic analysis, the gold standard imaging technique is the cardiac magnetic resonance. Adjunctive diagnostic tools as endomyocardial biopsy can be
Introduction Endomyocardial fibrosis (EMF) is a disease of unknown cause that was first described by Davies in Uganda in 1948.1 It is characterized by the development of restrictive cardiomyopathy, with the involvement of left or right ventricle or both. Although accurate epidemiologic data are lacking, EMF is estimated to be one of the more common forms of restrictive cardiomyopathy worldwide. Even though it is endemic in sub-Saharan Africa, cases of EMF have been described in Asia2 and South America.3 Then there is an increase in the EMF cases in the Western countries because of immigration.4,5 EMF is primarily a disease of the young, occurring in children, adolescents and young adults. In Africa, a bimodal peak at ages 10 and 30 years has been observed and the differences between sexes in the frequency of disease have been variable.6,7 Poverty, malnutrition, allergy, dietary factors, infective agents as Plasmodium species, Schistosoma , Epstein-Barr virus, Coxsackie B virus and Toxoplasma gondii, autoimmunity, toxic agents and heredity have been proposed as etiological factors.6–10 Abnormal eosinophils are involved in the pathogenesis,11 as eosinophilia is found in some cases of EMF, and similar endocardial fibrotic changes develop in patients with eosinophilic leukemia and Loffler disease.12 Moreover, it was observed that the presence of one or more family’s members with EMF corresponds to an increasing risk to be affected by EMF.6 The familial occurrence of EMF could be because of genetic or environmental factors or both, but future studies are needed to clarify this issue.
considered in ambiguous cases and can help in patient management. J Cardiovasc Med 2015, 16:547–551 Keywords: cardiac magnetic resonance, endomyocardial fibrosis, restrictive cardiomyopathy Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy Correspondence to Ilaria Dato, MD, Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy Tel: +39 6 3051166; fax: +39 6 3055535; e-mail: [email protected] Received 17 November 2013 Revised 8 May 2014 Accepted 8 May 2014
by the scar tissue, with consequent regurgitation, dilatation of atria, cardiomegaly and congestive heart failure. The clinical diagnosis of EMF is difficult to determine in the absence of cardiac failure. Davies described three phases of the disease in his patients from Uganda.1 The initial phase is an acute carditis phase, characterized by fever, abdominal distension, facial edema, periorbital swelling, body itching, and, in severe cases, by stroke, heart failure and shock. Those who survive this acute illness progress into a subacute phase followed by a chronic phase, consisting in right, left or bilateral heart failure. Right ventricular EMF is characterized by raised systemic venous pressure, which causes hepatomegaly, ascites, facial edema and jugular venous distension. In left ventricular EMF, there are signs of mitral regurgitation as dyspnea and orthopnea. The bilateral form is the most common form of EMF and is generally characterized by the predominance of right-sided lesions. Systolic murmur as a sign of tricuspid or mitral regurgitation can be detected. At the ECG, signs of atrial enlargement, left or right ventricle hypertrophy and overload are generally present, and in patients with large pericardial effusion, lowvoltage QRS can be detected. Moreover, tachyarrhythmia as atrial fibrillation and conduction abnormalities as atrioventricular and intraventricular blocks can occur. Finally, the migration of thrombi from either the atria or the ventricles can occur leading to thromboembolic complications as acute or chronic pulmonary thromboembolism and stroke.
Clinical presentation EMF is characterized by thickening of the ventricular endocardium with dense and white fibrous tissue, causing cavity obliteration and restriction of ventricular filling by blood. The atrioventricular valves are generally involved 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnostic tools Diagnosis is generally made by echocardiography and apex obliteration of the involved ventricle/s is the hallmark of the disease, along with dilated atrium/a with DOI:10.2459/JCM.0000000000000165
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
548 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
normal sized or mildly dilated ventricle/s.13,14 Mocumbi et al.6 elaborated a series of major and minor echocardiographic criteria for diagnosis of EMF, applied to a Mozambique population, for screening of EMF and grading of disease severity (Table 1).6 According to Mocumbi’s score system, EMF is diagnosed in the presence of two major criteria or one major criterion associated with two minor criteria. A total score of less than 8 indicates mild endomyocardial fibrosis, 8–15 moderate disease and more than 15 severe disease. These criteria can be used for family screening of EMF and for early identification of asymptomatic patients, allowing a prompt therapeutic strategy to improve their prognosis.14,15 EMF can be confused with the more common cardiomyopathies, as dilated (DCM), hypertrophic (HCM) and restrictive (RCM), with rheumatic valvular disease (RHD) and with constrictive pericarditis,13 and differential diagnosis can be difficult, especially in nonendemic countries. Obliteration of the apex in EMF should be distinguished from the apical type of HCM, in which obliteration of the apex occurs in systole only. Another feature of EMF is the involvement of atrioventricular valves. In the setting of clinically severe mitral or tricuspid regurgitation, the differential diagnosis of EMF from RHD is based on echocardiographic evidence of small or normal-size ventricle/s with grossly dilated atrium/a, on the contrary of RHD in which ventricle/s tend/s to be dilated. Also, the presence of normal-size ventricles helps to differentiate EMF from DCM. Differential diagnosis with RCM can be challenging and is based only on the presence of obliteration of the ventricular apex. Finally, in biventricular EMF, the hemodynamic findings of the cardiac catheterism can be similar to those of constrictive pericarditis, with the dip and plateau pattern of Table 1
Echocardiographic diagnostic criteria of endomyocardial
fibrosis Major criteria
Score
Endomyocardial plaques >2 mm in thickness Thin (1 mm) endomyocardial patches affecting more than one ventricular wall Obliteration of the right ventricular or left ventricular apex Thrombi or spontaneous contrast without severe venticular dysfunction Retraction of the right ventricular apex (right ventricular apical notch) Atrioventricular-valve dysfunction due to adhesion of the valvular apparatus to the ventricular wall Minor criteria
2 3 4 4 4 1–4a Score
Thin endomyocardial patches localized to one ventricular wall Restrictive flow pattern across mitral or tricuspid valves Pulmonary-valve diastolic opening Diffuse thickening of the anterior mitral leaflet Enlarged atrium with normal-size ventricle M-movement of the interventricular septum and flat posterior wall Enhanced density of the moderator or other intraventricular bands
1 2 2 1 2 1 1
See explanation in the text. a The score is assigned according to the severity of atrioventricular regurgitation. Modified from Mocumbi, Ferreira, Sidi, and Yacoub, 2008 (reference6).
restrictive ventricular filling. However, cardiac catheterism cannot show pressure equalization between ventricles, which is typical of constrictive pericarditis. Also in this case, the correct diagnoses should be based on the evidence of apical obliteration by echocardiography or ventriculography, and on the presence of normal pericardium thickness and severely dilated atria documented by echocardiography and cardiac magnetic resonance (CMR). Although echocardiography is able to detect characteristics of EMF typical of the advanced stages of EMF such as the obliteration of the right ventricular and/or left ventricular apex with endomyocardial thickening and/or calcification, and corresponding atrial dilatation,14 it cannot be useful in asymptomatic or paucisymptomatic subjects with mild structural and functional echocardiographic abnormalities, as well as in differentiating EMF from other cardiac diseases. CMR provides accurate information on ventricular morphology and function and is particularly useful in the characterization of right ventricle (Fig. 1). Moreover, in the differential diagnosis with DCM, the CMR offers an optimal visualization of the ventricular apex and possible apical thrombi, which are associated with normal or near-normal systolic function in EMF, differently from DCM. Late gadolinium enhancement (LGE)-CMR allows the assessment of myocardial inflammation, fibrosis and injury caused by a relative accumulation of gadolinium that occurs in these conditions as the result of slower washout kinetics and the increased extracellular volume. Precise EMF diagnosis and evaluation of fibrosis may allow surgical intervention in a less advanced stage of the disease to improve quality of life and prognosis. Salemi et al. published an interesting study on application of LGE-CMR for EMF diagnosis,16 confirmed by histopathologic analysis. They documented an endocardial distribution of LGE corresponding to fibrotic tissue, commonly extending from the subvalvular region to the apex of the ventricles, where it was usually more prominent. Then, a three-layered appearance was typical of this disease with an inner layer showing no perfusion because of presence of thrombus, a middle layer of LGE reflecting the fibrotic tissue and an outer layer of almost normal myocardium (Fig. 1). Subendocardial LGE can be caused by other conditions, such as amyloidosis, sarcoidosis and subendocardial infarction.17 In EMF, the LGE is subendocardial and heterogeneous, with hypointense areas represented by thrombus or calcification. It is frequently covered by an apical filling mass and extended to the inflow tract and subvalvular apparatus. However, in subendocardial infarction, the LGE is related to a coronary artery distribution, there is no apical filling mass, and if there is an apical involvement, there are wall thinning and wall motion abnormalities. In cardiac amyloidosis, there is a global, heterogeneous, subendocardial hyperenhancement associated with a global wall thickening and systolic dysfunction. In sarcoidosis, the LGE-MRI shows areas of
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
How to recognize endomyocardial fibrosis? Dato 549
Fig. 1
(a)
(b)
(c)
T
F
Left ventricular endomyocardial fibrosis: (a) four-chamber steady-state free precession, (b) late gadolinium enhancement showing thrombus (T) and fibrosis (F), (c) histologic confirmation. From Hamilton-Craig C et al. Non-tropical endomyocardial fibrosis by cardiovascular magnetic resonance, demonstrating the value of CMR in restrictive cardiomyopathy. Journal of Cardiovascular Magnetic Resonance 2011, 13 (Suppl 1); P281.
myocardial enhancement in regions with granulomas, which are characterized by wall thinning and wall motion abnormalities. These abnormalities are usually located in the septum, but can affect other walls, although papillary muscle and the right ventricle wall are rarely involved. Moreover, in sarcoidosis, hyperenhancement can also be midwall, epicardia or transmural. Finally, in left ventricular noncompaction, MRI shows a thickened apex with a double-layered appearance and marked trabeculations, which are associated to a nontransmural LGE.17 As in other cardiomyopathies, the early diagnosis of diastolic dysfunction has an important prognostic value and may impact the management strategy of patients with incipient heart failure. Although Doppler echocardiography remains the clinical reference for the evaluation of diastolic dysfunction, several CMR studies reported capabilities of this modality for the assessment of diastolic function. Several CMR techniques have been developed for evaluating diastolic function, including the volumetric filling curves,18 phase-contrast imaging,19 tagging20 and strain-encoded imaging.21 Quantitative CMR measurement of variables including Evel, Avel, E:A ratio and deceleration time are highly correlated with echocardiographic measurements.22,23 The role of endomyocardial biopsy (EMB) is controversial in the diagnosis of EMF.24 Histological features typical of EMF are extensive endocardial fibrous thickening, consisting of collagen fibers, with structural alterations and a predominance of collagen type I over type III, and small vessel proliferation, probably important for the maintenance of the fibrotic lesions,25 and mild-to-moderate inflammatory infiltrate, with predominance of macrophages and T-lymphocytes.8 Eosinophils may be sometimes found in the inflammatory infiltrates, associated with hypereosinophilia. Indeed, it has been speculated that eosinophil degranulation in the ventricular myocardium at early stages of EMF may promote local necrosis, inflammation and thrombosis that culminate in
scar tissue formation and endocardial thickening.26 It is common to find in histological specimens a superficial thrombotic layer and calcification associated to fibrotic tissue. Although EMB could be redundant in advanced stages of EMF, its application in asymptomatic or mild symptomatic patients with ambiguous echocardiographic abnormalities may help to obtain a right diagnosis, excluding other restrictive cardiomyopathies. Moreover, EMB can help in treatment strategy. In particular, in patients with clear evidence of inflammatory infiltrates at EMB, physicians may prescribe timely corticosteroid and immunomodulatory therapies, with consequent clinical and echocardiographic benefits.27 A diagnostic work flow is proposed in Fig. 2.6
Management The overall prognosis of EMF is poor and the survival of patients with EMF after diagnosis is reported to be 2 years. Death usually results from complications of chronic heart failure, but may also be caused by acute thromboembolism (pulmonary or cerebrovascular) and arrhythmia. EMF is usually managed by medical therapy and echocardiographic-guided drainage of pericardial, pleural and peritoneal effusions. In acute disease, oral corticoids are recommended for 7–10 days.28 Heart failure can be treated with diuretics, angiotensin-converting enzyme inhibitors and b-blockers. Digitals can be used to control heart rate in patients with atrial fibrillation. In selected patients, oral anticoagulants are usually started for the prevention of thromboembolism in atrial fibrillation and/or in the presence of ventricular or atrial thrombi. Surgery has been observed to increase survival and improve quality of life in patients with EMF in New York Heart Association class III and IV, in comparison with medical therapy alone.29 The surgery consists of resecting the fibrous endocardium and correcting the atrioventricular valve abnormalities. However, it has been associated with high morbidity and mortality, owing
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
550 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 2
Chronic left and/or right heart failure
Acute carditis (fever, abdominal distention, facial edema, heart failure, etc)
Asymptomatic (e.g.: family screening) or mild symptomatic patients (fever, effor dyspnea, palpitations, etc)
Echocardiography
Ventricle apex obliteration, dilated atrium/a with normal sized or mildly dilated ventricle/s
Diagnosis according Mocumbi’s score system*
Yes
Differential diagnosis (DCM, HCM, RCM, RHD and CP)
No
Medical and/or surgical treatment
Cardiac magnetic resonance
Subendocardial LGE 3-layer appearance
Yes
Differential diagnosis (DCM, HCM, RCM, CP, cardiac amyloidosis and sarcoidosis, etc)
No
Medical and/or surgical treatment
Endomyocardial biopsy
Histological features of EMF (e.g.: endocardial fibrosis, calcifications, thombus, inflammatory cells, etc)
Guided medical therapy (e.g.: corticosteroids)
Diagnostic work-flow of endomyocardial fibrosis. A definite diagnosis of endomyocardial fibrosis is made in the presence of two major criteria or one major criterion associated with two minor criteria. A total score of less than 8 indicates mild endomyocardial fibrosis, 8–15 moderate disease and more than 15 severe disease.6 DCM, dilated cardiomyopathy; HCM, hyperthophic cardiomyopathy; RCM, restrictive cardiomyopathy; RHD, rheumatic valvular disease; CP, constrictive pericarditis; LGE, late gadolinium enhancement; EMF, endomyocardial fibrosis.
to complications of valve replacement and extensive endocardial resection. Recently, new surgical approaches consisting in partial ventricular resection, with preservation of the valve apparatus and atrioventricular valve repair, and atrial size reduction have been introduced, although their benefits on long-term survival should be demonstrated.30 Moreover, recurrence after surgery has been documented.31
Conclusions EMF is a disease of unknown etiopathogenesis, whose diagnosis can be difficult especially in asymptomatic patients and in nonendemic countries. Echocardiographic diagnostic criteria are useful for initial diagnosis and screening of the disease. However, cardiac imaging techniques as CMR can help for differential diagnosis with other cardiomyopathies.
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How to recognize endomyocardial fibrosis? Dato 551
Future studies are needed to explore the mechanisms of the disease and to identify new therapeutic targets and improve the outcome of EMF.
References 1 2 3
4 5
6
7
8
9
10 11
12 13
14
15
16
17
18
Davies JNP. Endocardial Fibrosis in Africans. East Afr Med J 1948; 25:10– 14. Yin R. Endomyocardial fibrosis in China. Chin Med Sci J 2000; 15:55–60. Puigbo JJ, Combellas I, Acquatella H, et al. Endomyocardial disease in South America-report on 23 cases in Venezuela. Postgrad Med J 1983; 59:162–169. Pieroni M, Marzo F, Smaldone C, et al. Endomyocardial Fibrosis. J. Am. Coll. Cardiol 2010; 55:e137. Lo´pez Ramo´n M, Garcı´a de la Calzada MD, Domı´nguez Cunchillos M, Salazar Mena J. Tropical endomyocardial fibrosis in Spain. An Pediatr (Barc) 2013; 78:326–329. Mocumbi AO, Ferreira MB, Sidi D, Yacoub MH. A population study of endomyocardial fibrosis in a rural area of Mozambique. N Engl J Med 2008; 359:43–49. Rutakingirwa M, Ziegler JL, Newton R, Freers J. Poverty and eosinophilia are risk factors endomyocardial fibrosis (EMF) in Uganda. Trop Med Inter Health 1999; 4:229–235. D’Andretta Iglezias S, Benvenuti LA, Calabrese F, et al. Endomyocardial fibrosis: pathological and molecular findings of surgically resected ventricular endomyocardium. Virchows Arch 2008; 453:233–241. Ijaola O, Falase AO. Distribution of antibodies against Coxsackie B viruses, arboviruses and Toxoplasma gondii among patients with endomyocardial fibrosis (EMF) compared with normal subjects from EMF endemic and nonendemic zones of Nigeria. Afr J Med Sci 1990; 19:93–103. Mathai A, Kartha CC, Balakrishnan KG. Serum immunoglobulins in patients with endomyocardial fibrosis. Indian Heart J 1986; 38:470–472. Mayanga-Kizza H, Gerwing E, Rutakingirwa M, et al. Tropical endomyocardial fibrosis in Uganda: the tribal and geographic distribution, and the association with eosinophilia. Trop Cardiol 2000; 26:45–48. Brockington IF, Olsen EGJ. Loffler’s endocarditis and Davies’ endomyocardial fibrosis. Am Heart J 1973; 85:308–322. Hassan WM, Fawzy ME, Al Helaly S, et al. Pitfalls in diagnosis and clinical, echocardiographic, and hemodynamic findings in endomyocardial fibrosis. A 25-year experience. Chest 2005; 128:3985–3992. Berensztein CS, Pin˜eiro D, Marcotegui M, et al. Usefulness of echocardiography and Doppler echocardiography in endomyocardial fibrosis. J Am Soc Echocardiogr 2000; 13:385–392. Mocumbi AO, Carrilho C, Sarathchandra P, et al. Echocardiography accurately assesses the pathological abnormalities of chronic endomyocardial fibrosis. Int J Cardiovasc Imaging 2011; 27:955–964.
19
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25 26 27
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29 30
31
Salemi VM, Rochitte CE, Shiozaki AA, et al. Late gadolinium enhancement magnetic resonance imaging in the diagnosis and prognosis of endomyocardial fibrosis patients. Circ Cardiovasc Imaging 2011; 4:304–311. Mahrholdt H, Wagner A, Judd RM, et al. Delayed enhancement cardiovascular magnetic resonance assessment of nonischaemic cardiomyopathies. Eur Heart J 2005; 26:1461–1474. Kawaji K, Codella NC, Prince MR, et al. Automated segmentation of routine clinical cardiac magnetic resonance imaging for assessment of left ventricular diastolic dysfunction. Circ Cardiovasc Imaging 2009; 2:476–484. Bollache E, Redheuil A, Clement-Guinaudeau S, et al. Automated left ventricular diastolic function evaluation from phase-contrast cardiovascular magnetic resonance and comparison with Doppler echocardiography. J Cardiovasc Magn Reson 2010; 12:63. Fernandes VR, Edvardsen T, Rosen BD, et al. The influence of left ventricular size and global function on regional myocardial contraction and relaxation in an adult population free of cardiovascular disease: a tagged CMR study of the MESA cohort. J Cardiovasc Magn Reson 2007; 9:921–930. Neizel M, Korosoglou G, Lossnitzer D, et al. Impact of systolic and diastolic deformation indexes assessed by strain-encoded imaging to predict persistent severe myocardial dysfunction in patients after acute myocardial infarction at follow-up. J Am Coll Cardiol 2010; 56:1056–1062. Rathi VK, Doyle M, Yamrozik J, et al. Routine evaluation of left ventricular diastolic function by cardiovascular magnetic resonance: a practical approach. J Cardiovasc Magn Reson 2008; 10:3. Kudelka AM, Turner DA, Liebson PR, et al. Comparison of cine magnetic resonance imaging and Doppler echocardiography for evaluation of left ventricular diastolic function. Am J Cardiol 1997; 80:384–386. Barretto AC, Bellotti G, Higuchi Mde L, et al. Endomyocardial biopsy of the right ventricle in patients with endomyocardial fibrosis. Arq Bras Cardiol 1986; 46:19–21. Davies JNP, Ball JD. The pathology of endomyocardial fibrosis in Uganda. Br Heart J 1955; 17:337–359. Olsen EGJ, Spry CJF. Relation between eosinophilia and endomyocardial disease. Prog Cardiovasc Dis 1985; 27:241–254. Klion AD, Bochner BS, Gleich GJ, et al. The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006; 117:1292–1302. Mocumbi AOH, Falase AO. Recent advances in the epidemiology, diagnosis and treatment of endomyocardial fibrosis in Africa. Heart 2013; 99:1481–1487. Moraes F, Lapa C, Hazin S, et al. Surgery of endomyocardial fibrosis revisited. Eur J Cardio-Thorac Surg 1999; 15:309–313. Mocumbi AO, Carrilho C, Burke MM, et al. Emergency surgical treatment of advanced endomyocardial fibrosis in Mozambique. Nat Clin Pract Cardiovasc Med 2009; 62:10. Moraes CR, Buffolo E, Moraes Neto F, et al. Recurrence of fibrosis after endomyocardial fibrosis surgery. Arq Bras Cardiol 1996; 67:297–299.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
How to recognize endomyocardial fibrosis? Ilaria Dato Endomyocardial fibrosis is a disease of unknown cause, characterized by the development of restrictive cardiomyopathy. Although it is endemic in Africa, some cases have been described in Asia, South America and Europe, where a substantial unfamiliarity with this disease still exists. Moreover, differential diagnosis of endomyocardial fibrosis with other cardiomyopathies can be difficult, especially in asymptomatic patients and in initial stage of the disease. After initial echocardiographic analysis, the gold standard imaging technique is the cardiac magnetic resonance. Adjunctive diagnostic tools as endomyocardial biopsy can be
Introduction Endomyocardial fibrosis (EMF) is a disease of unknown cause that was first described by Davies in Uganda in 1948.1 It is characterized by the development of restrictive cardiomyopathy, with the involvement of left or right ventricle or both. Although accurate epidemiologic data are lacking, EMF is estimated to be one of the more common forms of restrictive cardiomyopathy worldwide. Even though it is endemic in sub-Saharan Africa, cases of EMF have been described in Asia2 and South America.3 Then there is an increase in the EMF cases in the Western countries because of immigration.4,5 EMF is primarily a disease of the young, occurring in children, adolescents and young adults. In Africa, a bimodal peak at ages 10 and 30 years has been observed and the differences between sexes in the frequency of disease have been variable.6,7 Poverty, malnutrition, allergy, dietary factors, infective agents as Plasmodium species, Schistosoma , Epstein-Barr virus, Coxsackie B virus and Toxoplasma gondii, autoimmunity, toxic agents and heredity have been proposed as etiological factors.6–10 Abnormal eosinophils are involved in the pathogenesis,11 as eosinophilia is found in some cases of EMF, and similar endocardial fibrotic changes develop in patients with eosinophilic leukemia and Loffler disease.12 Moreover, it was observed that the presence of one or more family’s members with EMF corresponds to an increasing risk to be affected by EMF.6 The familial occurrence of EMF could be because of genetic or environmental factors or both, but future studies are needed to clarify this issue.
considered in ambiguous cases and can help in patient management. J Cardiovasc Med 2015, 16:547–551 Keywords: cardiac magnetic resonance, endomyocardial fibrosis, restrictive cardiomyopathy Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy Correspondence to Ilaria Dato, MD, Institute of Cardiology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy Tel: +39 6 3051166; fax: +39 6 3055535; e-mail: [email protected] Received 17 November 2013 Revised 8 May 2014 Accepted 8 May 2014
by the scar tissue, with consequent regurgitation, dilatation of atria, cardiomegaly and congestive heart failure. The clinical diagnosis of EMF is difficult to determine in the absence of cardiac failure. Davies described three phases of the disease in his patients from Uganda.1 The initial phase is an acute carditis phase, characterized by fever, abdominal distension, facial edema, periorbital swelling, body itching, and, in severe cases, by stroke, heart failure and shock. Those who survive this acute illness progress into a subacute phase followed by a chronic phase, consisting in right, left or bilateral heart failure. Right ventricular EMF is characterized by raised systemic venous pressure, which causes hepatomegaly, ascites, facial edema and jugular venous distension. In left ventricular EMF, there are signs of mitral regurgitation as dyspnea and orthopnea. The bilateral form is the most common form of EMF and is generally characterized by the predominance of right-sided lesions. Systolic murmur as a sign of tricuspid or mitral regurgitation can be detected. At the ECG, signs of atrial enlargement, left or right ventricle hypertrophy and overload are generally present, and in patients with large pericardial effusion, lowvoltage QRS can be detected. Moreover, tachyarrhythmia as atrial fibrillation and conduction abnormalities as atrioventricular and intraventricular blocks can occur. Finally, the migration of thrombi from either the atria or the ventricles can occur leading to thromboembolic complications as acute or chronic pulmonary thromboembolism and stroke.
Clinical presentation EMF is characterized by thickening of the ventricular endocardium with dense and white fibrous tissue, causing cavity obliteration and restriction of ventricular filling by blood. The atrioventricular valves are generally involved 1558-2027 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnostic tools Diagnosis is generally made by echocardiography and apex obliteration of the involved ventricle/s is the hallmark of the disease, along with dilated atrium/a with DOI:10.2459/JCM.0000000000000165
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
548 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
normal sized or mildly dilated ventricle/s.13,14 Mocumbi et al.6 elaborated a series of major and minor echocardiographic criteria for diagnosis of EMF, applied to a Mozambique population, for screening of EMF and grading of disease severity (Table 1).6 According to Mocumbi’s score system, EMF is diagnosed in the presence of two major criteria or one major criterion associated with two minor criteria. A total score of less than 8 indicates mild endomyocardial fibrosis, 8–15 moderate disease and more than 15 severe disease. These criteria can be used for family screening of EMF and for early identification of asymptomatic patients, allowing a prompt therapeutic strategy to improve their prognosis.14,15 EMF can be confused with the more common cardiomyopathies, as dilated (DCM), hypertrophic (HCM) and restrictive (RCM), with rheumatic valvular disease (RHD) and with constrictive pericarditis,13 and differential diagnosis can be difficult, especially in nonendemic countries. Obliteration of the apex in EMF should be distinguished from the apical type of HCM, in which obliteration of the apex occurs in systole only. Another feature of EMF is the involvement of atrioventricular valves. In the setting of clinically severe mitral or tricuspid regurgitation, the differential diagnosis of EMF from RHD is based on echocardiographic evidence of small or normal-size ventricle/s with grossly dilated atrium/a, on the contrary of RHD in which ventricle/s tend/s to be dilated. Also, the presence of normal-size ventricles helps to differentiate EMF from DCM. Differential diagnosis with RCM can be challenging and is based only on the presence of obliteration of the ventricular apex. Finally, in biventricular EMF, the hemodynamic findings of the cardiac catheterism can be similar to those of constrictive pericarditis, with the dip and plateau pattern of Table 1
Echocardiographic diagnostic criteria of endomyocardial
fibrosis Major criteria
Score
Endomyocardial plaques >2 mm in thickness Thin (1 mm) endomyocardial patches affecting more than one ventricular wall Obliteration of the right ventricular or left ventricular apex Thrombi or spontaneous contrast without severe venticular dysfunction Retraction of the right ventricular apex (right ventricular apical notch) Atrioventricular-valve dysfunction due to adhesion of the valvular apparatus to the ventricular wall Minor criteria
2 3 4 4 4 1–4a Score
Thin endomyocardial patches localized to one ventricular wall Restrictive flow pattern across mitral or tricuspid valves Pulmonary-valve diastolic opening Diffuse thickening of the anterior mitral leaflet Enlarged atrium with normal-size ventricle M-movement of the interventricular septum and flat posterior wall Enhanced density of the moderator or other intraventricular bands
1 2 2 1 2 1 1
See explanation in the text. a The score is assigned according to the severity of atrioventricular regurgitation. Modified from Mocumbi, Ferreira, Sidi, and Yacoub, 2008 (reference6).
restrictive ventricular filling. However, cardiac catheterism cannot show pressure equalization between ventricles, which is typical of constrictive pericarditis. Also in this case, the correct diagnoses should be based on the evidence of apical obliteration by echocardiography or ventriculography, and on the presence of normal pericardium thickness and severely dilated atria documented by echocardiography and cardiac magnetic resonance (CMR). Although echocardiography is able to detect characteristics of EMF typical of the advanced stages of EMF such as the obliteration of the right ventricular and/or left ventricular apex with endomyocardial thickening and/or calcification, and corresponding atrial dilatation,14 it cannot be useful in asymptomatic or paucisymptomatic subjects with mild structural and functional echocardiographic abnormalities, as well as in differentiating EMF from other cardiac diseases. CMR provides accurate information on ventricular morphology and function and is particularly useful in the characterization of right ventricle (Fig. 1). Moreover, in the differential diagnosis with DCM, the CMR offers an optimal visualization of the ventricular apex and possible apical thrombi, which are associated with normal or near-normal systolic function in EMF, differently from DCM. Late gadolinium enhancement (LGE)-CMR allows the assessment of myocardial inflammation, fibrosis and injury caused by a relative accumulation of gadolinium that occurs in these conditions as the result of slower washout kinetics and the increased extracellular volume. Precise EMF diagnosis and evaluation of fibrosis may allow surgical intervention in a less advanced stage of the disease to improve quality of life and prognosis. Salemi et al. published an interesting study on application of LGE-CMR for EMF diagnosis,16 confirmed by histopathologic analysis. They documented an endocardial distribution of LGE corresponding to fibrotic tissue, commonly extending from the subvalvular region to the apex of the ventricles, where it was usually more prominent. Then, a three-layered appearance was typical of this disease with an inner layer showing no perfusion because of presence of thrombus, a middle layer of LGE reflecting the fibrotic tissue and an outer layer of almost normal myocardium (Fig. 1). Subendocardial LGE can be caused by other conditions, such as amyloidosis, sarcoidosis and subendocardial infarction.17 In EMF, the LGE is subendocardial and heterogeneous, with hypointense areas represented by thrombus or calcification. It is frequently covered by an apical filling mass and extended to the inflow tract and subvalvular apparatus. However, in subendocardial infarction, the LGE is related to a coronary artery distribution, there is no apical filling mass, and if there is an apical involvement, there are wall thinning and wall motion abnormalities. In cardiac amyloidosis, there is a global, heterogeneous, subendocardial hyperenhancement associated with a global wall thickening and systolic dysfunction. In sarcoidosis, the LGE-MRI shows areas of
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
How to recognize endomyocardial fibrosis? Dato 549
Fig. 1
(a)
(b)
(c)
T
F
Left ventricular endomyocardial fibrosis: (a) four-chamber steady-state free precession, (b) late gadolinium enhancement showing thrombus (T) and fibrosis (F), (c) histologic confirmation. From Hamilton-Craig C et al. Non-tropical endomyocardial fibrosis by cardiovascular magnetic resonance, demonstrating the value of CMR in restrictive cardiomyopathy. Journal of Cardiovascular Magnetic Resonance 2011, 13 (Suppl 1); P281.
myocardial enhancement in regions with granulomas, which are characterized by wall thinning and wall motion abnormalities. These abnormalities are usually located in the septum, but can affect other walls, although papillary muscle and the right ventricle wall are rarely involved. Moreover, in sarcoidosis, hyperenhancement can also be midwall, epicardia or transmural. Finally, in left ventricular noncompaction, MRI shows a thickened apex with a double-layered appearance and marked trabeculations, which are associated to a nontransmural LGE.17 As in other cardiomyopathies, the early diagnosis of diastolic dysfunction has an important prognostic value and may impact the management strategy of patients with incipient heart failure. Although Doppler echocardiography remains the clinical reference for the evaluation of diastolic dysfunction, several CMR studies reported capabilities of this modality for the assessment of diastolic function. Several CMR techniques have been developed for evaluating diastolic function, including the volumetric filling curves,18 phase-contrast imaging,19 tagging20 and strain-encoded imaging.21 Quantitative CMR measurement of variables including Evel, Avel, E:A ratio and deceleration time are highly correlated with echocardiographic measurements.22,23 The role of endomyocardial biopsy (EMB) is controversial in the diagnosis of EMF.24 Histological features typical of EMF are extensive endocardial fibrous thickening, consisting of collagen fibers, with structural alterations and a predominance of collagen type I over type III, and small vessel proliferation, probably important for the maintenance of the fibrotic lesions,25 and mild-to-moderate inflammatory infiltrate, with predominance of macrophages and T-lymphocytes.8 Eosinophils may be sometimes found in the inflammatory infiltrates, associated with hypereosinophilia. Indeed, it has been speculated that eosinophil degranulation in the ventricular myocardium at early stages of EMF may promote local necrosis, inflammation and thrombosis that culminate in
scar tissue formation and endocardial thickening.26 It is common to find in histological specimens a superficial thrombotic layer and calcification associated to fibrotic tissue. Although EMB could be redundant in advanced stages of EMF, its application in asymptomatic or mild symptomatic patients with ambiguous echocardiographic abnormalities may help to obtain a right diagnosis, excluding other restrictive cardiomyopathies. Moreover, EMB can help in treatment strategy. In particular, in patients with clear evidence of inflammatory infiltrates at EMB, physicians may prescribe timely corticosteroid and immunomodulatory therapies, with consequent clinical and echocardiographic benefits.27 A diagnostic work flow is proposed in Fig. 2.6
Management The overall prognosis of EMF is poor and the survival of patients with EMF after diagnosis is reported to be 2 years. Death usually results from complications of chronic heart failure, but may also be caused by acute thromboembolism (pulmonary or cerebrovascular) and arrhythmia. EMF is usually managed by medical therapy and echocardiographic-guided drainage of pericardial, pleural and peritoneal effusions. In acute disease, oral corticoids are recommended for 7–10 days.28 Heart failure can be treated with diuretics, angiotensin-converting enzyme inhibitors and b-blockers. Digitals can be used to control heart rate in patients with atrial fibrillation. In selected patients, oral anticoagulants are usually started for the prevention of thromboembolism in atrial fibrillation and/or in the presence of ventricular or atrial thrombi. Surgery has been observed to increase survival and improve quality of life in patients with EMF in New York Heart Association class III and IV, in comparison with medical therapy alone.29 The surgery consists of resecting the fibrous endocardium and correcting the atrioventricular valve abnormalities. However, it has been associated with high morbidity and mortality, owing
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550 Journal of Cardiovascular Medicine 2015, Vol 16 No 8
Fig. 2
Chronic left and/or right heart failure
Acute carditis (fever, abdominal distention, facial edema, heart failure, etc)
Asymptomatic (e.g.: family screening) or mild symptomatic patients (fever, effor dyspnea, palpitations, etc)
Echocardiography
Ventricle apex obliteration, dilated atrium/a with normal sized or mildly dilated ventricle/s
Diagnosis according Mocumbi’s score system*
Yes
Differential diagnosis (DCM, HCM, RCM, RHD and CP)
No
Medical and/or surgical treatment
Cardiac magnetic resonance
Subendocardial LGE 3-layer appearance
Yes
Differential diagnosis (DCM, HCM, RCM, CP, cardiac amyloidosis and sarcoidosis, etc)
No
Medical and/or surgical treatment
Endomyocardial biopsy
Histological features of EMF (e.g.: endocardial fibrosis, calcifications, thombus, inflammatory cells, etc)
Guided medical therapy (e.g.: corticosteroids)
Diagnostic work-flow of endomyocardial fibrosis. A definite diagnosis of endomyocardial fibrosis is made in the presence of two major criteria or one major criterion associated with two minor criteria. A total score of less than 8 indicates mild endomyocardial fibrosis, 8–15 moderate disease and more than 15 severe disease.6 DCM, dilated cardiomyopathy; HCM, hyperthophic cardiomyopathy; RCM, restrictive cardiomyopathy; RHD, rheumatic valvular disease; CP, constrictive pericarditis; LGE, late gadolinium enhancement; EMF, endomyocardial fibrosis.
to complications of valve replacement and extensive endocardial resection. Recently, new surgical approaches consisting in partial ventricular resection, with preservation of the valve apparatus and atrioventricular valve repair, and atrial size reduction have been introduced, although their benefits on long-term survival should be demonstrated.30 Moreover, recurrence after surgery has been documented.31
Conclusions EMF is a disease of unknown etiopathogenesis, whose diagnosis can be difficult especially in asymptomatic patients and in nonendemic countries. Echocardiographic diagnostic criteria are useful for initial diagnosis and screening of the disease. However, cardiac imaging techniques as CMR can help for differential diagnosis with other cardiomyopathies.
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How to recognize endomyocardial fibrosis? Dato 551
Future studies are needed to explore the mechanisms of the disease and to identify new therapeutic targets and improve the outcome of EMF.
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