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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3715_Библиотеки_им_академика_М_И_Перельмана
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9.2 Endomyocardial Fibrosis
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Table 9.1 Clinical, echocardiographic, biochemical, and haemodynamic criteria of constrictive
pericarditis versus restrictive cardiomyopathy/tropical endomyocardial brosis
Restrictive cardiomyopathy/
Variables Constrictive pericarditis
Physical examination
Pulmonary congestion Usually absent Usually present
Prominent Y descent in
jugular venous pulse
Pulsus Paradoxus ~1/3rd of patients Absent
Early diastolic sound Pericardial knock S3 (low pitched)
Echocardiographic/Doppler echocardiographic/Speckle tracking echocardiographic
ndings
Atrial size ±atrial enlargement
Left ventricular myocardium Normal “Sparkling” in amyloidosis
Respiratory variation in mitral
E wave velocity
Mitral valve ow pattern Restricted Restricted
Early diastolic mitral annular
velocity
Tissue Doppler E velocity Increased Reduced
Septal “bounce” Present Absent
Ventricular wall thickness Normal frequently increased
Speckle tracking
echocardiography
Thickness of the Pericardium >2mm (but <2mm in 15%) <2mm
Biomarkers
BNP <200pg/ml >600pg/ml
Haemodynamics
CVP tracing: Y descent Present Variable
Filling pressure ≥5mmHg Rare Common
Systolic pulmonary artery
pressure
Pulmonary capillary
wedge-right atrial pressure
“Square root” sign Present Variable
Reciprocal respiratory
variation in RV:LV peak
systolic pressure
Respiratory variation in
left-right pressure/ow PA,
PCW, RA
BNP B-type natriuretic peptide, CVP central venous pressure, RV right ventricle, LV left ventricle,
PA pulmonary artery, PCW pulmonary capillary wedge, RA right atrium
Present Variable
(LA>RA)
>25% <20%
≥8cm/sec <8cm/sec
Normal longitudinal,
decreased global
circumferential mechanics
<50mmHg ≥60mmHg
<5mmHg ≥5mmHg
Present Absent
Exaggerated Normal
endomyocardial brosis
Biatrial enlargement
May be asymmetric
Uniformly decreased
longitudinal, mild reduction in
circumferential mechanics
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
i. The Unitarian theory of Olsen. Olsen argued that both tropical endomyocardial
brosis and Loefer’s eosinophilic myocardial disease are the result endomyocardial damage caused by eosinophil breakdown products. Other investigators
have refuted this hypothesis [175, 177, 218, 254, 255].
ii. Based on serological studies in Nigeria, Falase believed that endomyocardial
brosis is the sequel of a previous episode of myocarditis caused by Toxoplasma
gondii. This view has been challenged as endomyocardial brosis is a distinct
clinico-pathological entity whereas toxoplasmosis is an opportunistic infection [68].
iii. Shaper in 1993 hypothesized that tropical endomyocardial brosis is a type of
Loefer’s endomyocardial disease and is secondary to immunological reaction
to some specic organism causing pancarditis and subsequent brosis [200].
iv. Valiathan and associates proposed a geochemical hypothesis, because endo-
myocardial brosis is prevalent in tropical belt having latasolic soil rich in the
mineral monazite [254, 255]. The presence of a lower concentration of magnesium and enhanced level of cerium in endomyocardial tissue suggest that
replacement of magnesium by cerium could be detrimental to cardiac energetics
[254, 255]. This hypothesis is supported by observations of higher uptake of
cerium by rat myocardium rather than skeletal muscle, stimulation of collagen
synthesis by cerium, substitution of magnesium by cerium and enhancement in
the level of cerium by magnesium deciency [108, 167, 219, 220, 254, 255].
Accordingly, the morphological similarity of hearts in endomyocardial brosis,
Loefer’s disease and methysergide toxicity is not the result of an identical
cause for which there is little evidence; it may, however, represent a similar
response of the heart to organic or inorganic stimuli which trigger myocyte
degeneration and interstitial proliferation. This hypothesis awaits conrmation
in an animal model [254, 255].
9.2.4 Cardiac Lesions
The basic feature is signicant endocardial brosis that obliterates the trabecular
pattern in ventricles. In its diffuse form, the brosis involves the entire inow, apex
and papillary muscles obliterating the ventricular cavity. The atrioventricular valve
leaets remain thin and are not usually involved in the disease process [108].
However, patchy brosis involving the papillary muscles tether the posterior mitral
leaet or subvalvular apparatus of the tricuspid valve, causing mitral or tricuspid
regurgitation. The right atrial enlargement may reach gigantic proportions, with formation of intracavitary thrombi. The ventricular outow tract is typically spared in
the great majority of cases [49–51, 108, 175, 177].
Interestingly, a striking feature is increased interstitial cellularity, with inammatory and thrombotic changes in biopsy samples from the contralateral ventricle
which signals reactive stromal change as the primary response in endomyocardial
brosis [108].
9.2 Endomyocardial Fibrosis
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On microscopic examination, the endocardium is divided into a supercial layer
of dense collagenous tissue with sparse hyalinization or calcication, and a deeper,
spongy layer consisting of capillary channels and lymphocytic inltrates.
Eosinophils are rarely seen. The subendocardial myobrils show degenerative
changes and focal scarring. At times, occlusive arteriopathy or dilated lymphatics
may be seen. The ultrastructural features include hypertrophic and atrophic changes
in myocytes, interstitial brosis, and signicant thickening of the capillary basement membrane [108]. Among 30 cases of endomyocardial brosis reported by
Seth and associates, 17 had interstitial brosis, 12 had myocytolysis, and 11 had
lymphocytic inltrates, while none showed eosinophilic inltration [222, 242].
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9.2.5 Clinical Presentation
Symptoms and physical ndings depend closely on severity of diastolic ventricular
dysfunction, and mitral or tricuspid valve incompetence.
9.2.6 Right Ventricular Endomyocardial Fibrosis
Gradual obliteration of the right ventricular inow, apex and cavity leads to
non-hypertensive tricuspid regurgitation. Clinical examination reveals sinus tachycardia, irregular pulse, normal arterial blood pressure, elevated jugular venous pressure, pulsatile hepatomegaly, pedal oedema, ascites precox, and cachexia.
There may be cardiomegaly due to right atrial or left atrial enlargement with or
without concomitant pericardial effusion, silent precordium, and third heart sound
(S3) with no murmur or rub.
9.2.7 Left Ventricular Endomyocardial Fibrosis
The clinical features are dependent on the severity of mitral regurgitation. Patients
may have a left ventricular type of cardiomegaly, evidence of pulmonary hypertension due to diastolic dysfunction, and a soft pansystolic murmur of mitral
regurgitation.
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
9.3 Investigations
9.3.1 Chest Radiography andFluoroscopy
Patients with predominant right ventricular endomyocardial brosis may show
presence of patchy endomyocardial calcication, better appreciated by uoroscopy,
and severe cardiomegaly in the presence of pericardial effusion [5, 25–32, 52, 81,
126, 127, 138, 139, 202, 238].
9.3.2 Electrocardiogram
Right ventricular involvement shows right axis deviation, right atrial enlargement,
and low voltage QRS complex. Atrial brillation is a common nding. Left ventricular endomyocardial brosis shows left axis deviation, large R voltage in V5, V6
and marked ST-depression with T wave inversion in V5, V6 [238].
9.3.3 Echocardiogram
The sine qua non of right ventricular endomyocardial brosis is a reduced ventricular cavity with an apical notch, deposition of brous tissue over the ventricular
endomyocardium, an adherent tricuspid valve, giant right atrium, preserved left
ventricular wall thickness, and left ventricular wall contractility. Additional ndings
may be layered organized thrombus over the brous tissue and non-hypertensive
tricuspid regurgitation. Pericardial effusion may be present.
The features of left ventricular disease include patchy involvement of endocardium, mitral regurgitation, pulmonary hypertension, presence of endocardial calcication, plastering of posterior mitral leaet and obliteration of apex [238, 241, 254,
255, 260–262].
9.3.4 Cardiac Magnetic Resonance Imaging
Soft tissue characterization helps differentiate apical hypertrophic cardiomyopathy
from brotic deposits of endomyocardial brosis [6, 7, 254, 255, 260, 261].
9.3 Investigations
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9.3.5 Haemodynamics andAngiographic Studies
In the right ventricle, early angiographic changes are characterized by alteration of
trabecular pattern at the apex with irregular, small lling defects along the septum,
later followed by effacement of normal trabeculae and obliteration of ventricular
apex. In later stages, the right ventricular inow becomes involved as well [40]. The
presence of thrombi appear as lling defects in massively enlarged right atrium.
In the left ventricle, the sequence of changes include loss of ne trabeculations
initially, followed by obliteration of apex and distal parts of the body evident as
appearance of contrast in crevices and outpouchings of a distorted cavity [222].
Mitral regurgitation ensues once the chordae and papillary muscles become
adherent.
In right ventricular endomyocardial brosis, the right ventricular pressure tracing may show a dip and plateau pattern. At an advanced stage, there is appearance
of tricuspid regurgitation and a rise in pulmonary artery pressure.
Similarly, in left ventricular endomyocardial brosis, a dip and plateau type of
pressure tracing is seen with a gradual increase in left ventricular end-diastolic pressure and pulmonary artery pressure. In biventricular involvement, the haemodynamic changes reect the pattern on the dominant side [6, 7, 254, 255, 260, 261].
9.3.6 Endomyocardial Biopsy
Endomyocardial biopsy helps to conrm the diagnosis of endomyocardial brosis.
The presence of dense collagenous tissue, organized thrombi, and focal inammatory cells seen in endomyocardial brosis helps to differentiate it from other types
of restrictive cardiomyopathy [6, 7, 237, 254, 255, 260, 261].
9.3.7 Treatment
Patients in NewYork Heart Association class I or IIare managed with medical therapy on the lines of chronic heart failure. Surgical treatment is mandatory for patients
in NewYork Heart Association class III and IV [6, 7, 222, 238, 241, 254, 255,
260–262].
The surgical treatment is the resection of brosed endocardium. The mitral and
tricuspid valves may require replacement, depending on the severity of involvement
[54]. Encouraging initial results have been reported for the technique of endocardiectomy and valvular reconstruction developed by Oliveira. However, the long-term
results in advanced stages of right ventricular involvement are awaited [177].
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
9.3.8 Results
With medical management, the 10year survival has been reported between 26% to
37%. The operative mortality in the published literature ranges from 16% to 20%
[6–8, 75, 136, 142, 143, 254, 255, 260, 261]. The present consensus is to recommend surgery for patients in NYHA class III and IV as excellent functional improvement occurs in majority of surgical survivors [254, 255, 260, 261].
9.4 Cardiac Amyloidosis
9.4.1 Denition
Amyloidosis is a multi-system disorder that is characterized by abnormal, extracellular deposition of amyloid leading to increased cardiac stiffness, restrictive cardiomyopathy, and multi organ dysfunction [41, 223, 269].
9.4.2 Classication
Depending on the precursor protein of origin, there are three common types of cardiac amyloidosis: (i) primary amyloidosis (light chain immunoglobulin, AL 74%),
(ii) senile wild type transthyretin (ATTR Wt, 22%), and (iii) mutant transthyretin
(familial, 40%). Other rare types are: (i) senile (serum amyloid A), and (ii) isolated
atrial natriuretic peptide related amyloidosis [10, 269].
9.4.3 Incidence
The incidence of primary amyloidosis is 6–10 per million population in North
America; the exact incidence from India is unknown [10].
9.4.4 Pathophysiology
The amyloid deposits comprise brillary and non-brillary components. The brillary component is a long, unbranched, beta-pleated, 7–10nm protein whereas the
non-brillary component includes amyloid P component, glycosaminoglycan
(GAG), etc. [110]. Extracellular deposition of amyloid leads to P38 protein kinase
9.4 Cardiac Amyloidosis
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mediated cellular dysfunction, oxidative stress, and apoptosis of cardiac myocytes [224].
Abnormal amyloid deposition may occur in small vessels, conduction system,
ventricular walls and other cardiac structures. Only up to 5% patients with wild type
transthyretin amyloidosis have extracardiac involvement. Whereas up to 40% of
patients of primary and mutant transthyretin amyloidosis have extracardiac disease.
There occurs direct metabolic dysfunction in primary amyloidosis wherein light
chain immunoglobulin bind to cardiac myocytes [224].
Cardiac involvement in amyloidosis is characterized by a reduced or relatively
normal ventricular cavity with markedly thickened ventricular walls leading to right
sided or biventricular heart failure. This results in low cardiac output with elevated
end-diastolic pressure, pulmonary and systemic venous congestion.
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9.4.5 Primary AL Amyloidosis
There is deposition of abnormal light chain immunoglobulin derived amyloid.
Patients present in the fth to sixth decade of life. Cardiac involvement is the second
most common site of involvement after renal. The median survival after development of clinically apparent heart failure and no AL guided treatment is around
8months [160]. The toxic component of the amyloid light chain is responsible for
severe cardiac dysfunction without apparent deposition in the cardiac muscle. This
contrasts with transthyretin related amyloidosis where the inltrative component
causes damage resulting in massive cardiomegaly at presentation. Macroglossia/
peri-orbital petechial lesions are considered pathognomonic of primary amyloidosis
in the proper clinical setting [160].
9.4.6 Familial Amyloidosis
This is characterized by mutant transthyretin derived amyloid deposits in different
tissues. More than 80 types of transthyretin mutations are found. It presents during
the third to sixth decade of life, depending on the type of mutation. The most common mutation responsible is Va1122Ile. Neuropathy and renal involvement predominate. Cardiac involvement occurs in a quarter of patients [190].
9.4.7 Senile Systemic Amyloidosis
This has wild-type transthyretin. Extracardiac involvement is rare. Presentation is
usually late in the seventh decade of life. About a quarter of the population beyond
80years of age has deposition of wild-type transthyretin derived amyloid deposits
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
in their hearts, but the clinical relevance of this is not known. Patients may also have
carpal tunnel syndrome [190].
Other types like secondary amyloidosis and atrial natriuretic peptide related
amyloidosis are rarely associated with cardiac involvement.
9.4.8 Clinical Presentation
The clinical presentation of cardiac amyloidosis mimics restrictive cardiomyopathy,
endomyocardial brosis, and constrictive pericarditis. Initial presentation is shortness of breath on accustomed exertion followed by right-sided failure, pedal oedema,
ascites and raised jugular venous pulse. The third space uid accumulation in AL
amyloidosis may be due to nephrotic syndrome with proteinuria.
In the later phase, patients may present with syncope, arrhythmia, electromechanical dissociation, or thromboembolic phenomenon. Some patients may present
with angina due to coronary involvement. Clinically, one should look for systemic
involvement in cardiac amyloidosis. These include macroglossia, periorbital purpuric lesions (raccoon eyes), subtle petechial lesions over the body (secondary to fragile blood capillaries, and co-existing factor X deciency), carpal-tunnel syndrome,
and autonomic neuropathy. Hepatomegaly present in the initial phase is due to amyloid deposit; in a later phase, it results from right heart failure, mimicking constrictive pericarditis and restrictive cardiomyopathy. Sudden cardiac death can occur in
30–40% of patients with amyloidosis due to electromechanical dissociation and
ventricular arrhythmias [191].
9.4.9 Diagnosis
9.4.9.1 Electrocardiogram
The ndings of low voltage QRS complexes in limb leads, pseudoinfarction pattern
in chest leads, poor R-wave progression, intraventricular conduction abnormalities,
atrioventricular block, and atrial brillation give clues to the diagnosis [38].
9.4.9.2 Echocardiography
Biatrial enlargement, thickened interatrial septum (>7mm), thickened interventricular septum (>12mm), concentric left ventricular wall thickening in the absence of
systemic hypertension, valvular thickening, and pericardial effusion are commonly
found on echocardiographic examination. Pulmonary artery hypertension may also
be present. A ventricular septal thickness of more than 15 mm indicates poor
9.4 Cardiac Amyloidosis
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prognosis. The ndings of “granular” or “sparkling” appearance of the ventricular
wall, although a classic feature of cardiac amyloidosis, is less specic [42, 140, 165].
9.4.9.3 Cardiac Magnetic Resonance Imaging andRadionuclide Study
Cardiac magnetic resonance imaging is helpful in equivocal cases before proceeding with endomyocardial biopsy. Late subendothelial gadolinium enhancement in
patients with a controlled heart rate is a diagnostic feature of amyloidosis.
Diphosphonate (DPD) or pyrophosphate (PVP) based nuclear imaging helps in
transthyretin related amyloidosis [69, 110, 111]. The non-brillary part of the amyloid P component can be targeted for identication of amyloid deposits in the body.
Due to cardiac movement, scintigraphy cannot accurately identify cardiac amyloid
deposition [110, 111].
9.4.9.4 Cardiac Biomarkers
B-type natriuretic peptide more than 600pg/ml in case of amyloidosis implies cardiac involvement [110]. Brain natriuretic peptide (BNP), N terminal fragment of
BNP (NT-ProBNP), troponin, and serum free light chains (FLC) have renal clearance, and can be falsely elevated in renal involvement due to amyloid [110].
Administration of lenalidomide and thalidomide, new drugs used in therapy, can
cause a transient increase in biomarkers.
9.4.9.5 Serologic Testing
Urine protein electrophoresis (UPEP) with immunoxation, combined with serum
FLC assay, detects abnormal monoclonal protein in almost all cases of primary
(AL) amyloidosis.
9.4.9.6 Endomyocardial Biopsy
Endomyocardial biopsy is useful to differentiate different types of cardiac amyloidosis. In primary amyloidosis (AL), biopsy of the abdominal fat pad, salivary gland,
rectal mucosa, and bone marrow obviates the need of endomyocardial biopsy.
Proteomic analysis and mass spectrometry sometimes accurately identify various
types of amyloidosis [225, 263].
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9.4.10 Treatment
Management of cardiac amyloidosis requires coordination between cardiology and
haematology/oncology, and includes management of congestive heart failure,
reduction of amyloid production, dissolution of already deposited amyloid, and
organ transplant. Diuretics are the mainstay of treatment.
Abnormal afnity of amyloid to calcium channel blockers and digoxin increases
the toxicity of these drugs and is poorly tolerated. Angiotensin receptor blockers,
and angiotensin converting enzyme inhibitors may not be tolerated because of coexisting renal dysfunction and autonomic neuropathy.
Overdose of diuresis, postural hypotension and autonomic neuropathy can cause
syncope. Midodrine is useful in patients with coexisting autonomic neuropathy. A
combination of frusemide and spironolactone is well tolerated.
For conduction abnormalities of the heart, no specic guidelines are present. For
symptomatic bradycardia, a pacemaker is indicated. Due to amyloid inltration, a
higher threshold of pacing is required. Amiodarone is a suitable medication, preferable to an automatic implantable cardioverter debrillator for electromechanical
dissociation.
9.4.10.1 Reduction inProduction ofAmyloid
Cardiac Amyloidosis
The treatment strategies of cardiac amyloidosis have evolved and are based on antiplasma cell therapy. Choosing an optimal treatment strategy as adopted in “modied Mayo staging” depends on the load of plasma cell clone, cardiac and renal
functional status, and associated conditions like neuropathy [112]. Based on the
available evidence, a combination of new antimyeloma drugs including proteasome
inhibitors (bortezomib) and immunomodulatory agents (thalidomide, lenalidomide)
is the best choice of therapy for cardiac amyloidosis without severe neuropathy.
Alternative regimens consisting of lenalidomide/pomalidomide are available for
those not tolerating the above regimen. Newer drugs originally approved for
myeloma, such as carlzomib and daratumumab, are being investigated for
amyloidosis.
The aim of initial induction therapy (bortezomib based) is to minimize the amyloid burden and eliminate plasma cells in bone marrow producing light chains.
Thereafter, cardiac transplantation, followed by high-dose chemotherapy with melphalan is considered. Autologous hematopoietic stem cell transplantation (ASCT)
is timed around 6months post transplantation [224].
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