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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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9.4 Cardiac Amyloidosis
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9.4.10.2 Transthyretin-Related Amyloidosis
Since the site of production of mutant transthyretin is in the liver, liver transplantation is performed before the development of signicant cardiomyopathy. Survival at
5years after liver transplantation is 75%. However, patients with mutation at VI22I
do not benet from liver transplantation as progression of cardiomyopathy continues due to the deposition of wild-type transthyretin over previous scaffolding of
mutant transthyretin [65, 74].
9.4.10.3 Novel Strategies
Tetramer stabilizers, that stabilize transthyretin (TTR) in its tetrameric form,
Diunisal (an NSAID), and Tafamidis, can halt amyloidogenesis.
Drugs that act at the level of gene expression, small interfering RNA (siRNA)
that inhibits the messenger RNA (mRNA) of transthyretin, and anti-sense oligonucleotides that damage the mRNA [179] are under investigation for decreasing the
production of mutant transthyretin.
Strategies aimed at disrupting the already deposited amyloid, such as monoclonal antibodies against SAP, a non-brillary constituent of amyloid, and doxycycline
are experimental.
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9.4.10.4 Cardiac Transplantation
Cardiac amyloidosis is not considered a priority indication for cardiac transplantation, given the shortage of donor hearts and relatively higher mortality. Cardiac
transplantation is preceded by induction therapy to reduce the light chain load, and
followed by ASCT, yielding a ve-year survival of 60%. Heart transplantation is
combined with liver transplantation in transthyretin amyloidosis [55, 56, 65,
270, 271].
9.4.11 Results
The overall 5 years survival in 346 European patients with cardiac amyloidosis
ranged between 40 and 94months [55, 56, 65, 270, 271]. The median overall survival in the Mayo Clinic group ranged from 94months in stage I cardiac amyloidosis to 6months in stage IV disease, categorized according to NT-proBNP, troponin
(I or C) and serum free light chains. Severe NT-proBNP elevation along with arterial
hypotension carries poor prognosis. The median survival is reported to be 6months
in AL variant compared to 24–66months in wild-transthyretin variant [43, 112].
A bortezomib based regimen is the rst choice (except in patients with severe
neuropathy). In combination with dexamethasone, it has a hematologic response
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
rate of 68–77%. Addition of cyclophosphamide increases the response rate to 94%.
Standard dose melphalan based regimens have response rates of 50–71%.
9.5 Restrictive Cardiomyopathy
9.5.1 Denition
Restrictive cardiomyopathy is a group of heterogenous myocardial diseases, characterized by increased ventricular stiffness leading to impaired ventricular lling.
9.5.2 Aetiology
The aetiology includes inltrative and non-inltrative disorders, storage disorders,
and idiopathic causes (Table9.2) [138].
9.5.3 Clinical Presentation
Patients may present with left-sided or right-sided heart failure. Patients with diastolic heart failure present with lethargy, fatigability, breathlessness, and pedal
oedema. Arrhythmias and heart block may produce palpitations and syncope.
Children exhibit poor growth because of underlying restrictive cardiomyopathy.
Underlying systemic diseases causing restrictive cardiomyopathy can have predominant symptoms at presentation, as enumerated in Tables 9.3 and 9.4. Characteristic
clinical signs such as elevated jugular venous pulsation with Kussmaul’s sign, ascites, peripheral oedema, and S3 and S4 gallops point towards congestive heart failure.
9.5.4 Diagnosis
9.5.4.1 Electrocardiogram
T.Hayashi and associates elaborated the following electrocardiographic ndings in
restrictive cardiomyopathy [88]:
i. Left or right atrial enlargement
ii. Atrial brillation and utter
iii. Atrial and ventricular ectopics
iv. Low voltage QRS complexes (Inltrative cardiomyopathy)
9.5 Restrictive Cardiomyopathy
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Table 9.2 Aetiology of restrictive cardiomyopathy
Acquisition
mode Genetic perturbations
Inltrative
Amyloidosis Acquired/
inherited
Sarcoidosis Acquired
Primary hyperoxaluria Inherited AGXT (type 1), GRHPR (type 2),
Storage diseases
Fabry disease Inherited GLA
Gaucher disease Inherited GBA
Hereditary hemochromatosis Inherited HAMP, HFE, HFE2, HJV, PNPLA3,
Glycogen storage disease Inherited Per specic type
Mucopolysaccharidosis type I (Hurler
syndrome)
Mucopolysaccharidosis type II (Hunter
syndrome)
Niemann-Pick disease Inherited NPC1, NPC2, SMPD1
Non-inltrative
Idiopathic Acquired
Diabetic cardiomyopathy Acquired
Scleroderma Acquired
Myobrillar myopathies Inherited BAG3, CRYAB, DES, DNAJB6, FHL1,
Pseudoxanthoma elasticum Inherited ABCC6
Sarcomeric protein disorders Inherited ACTC, β-MHC, TNNT2, TNNI3,
Werner’s syndrome Inherited WRN
Endomyocardial
Carcinoid heart disease Acquired
Endomyocardial brosis
Idiopathic Acquired
Hypereosinophilic syndrome Acquired
Chronic eosinophilic leukemia Acquired
Drugs (serotonin, methysergide,
ergotamine, mercurial agents, busulfan)
Endocardial broelastosis Inherited BMP5, BMP7, TAZ
Consequence of cancer/cancer
therapy
Metastatic cancer Acquired
Drugs (anthracyclines) Acquired
Radiation Acquired
Cited from Muchtar etal. [138]
Inherited IDUA
Inherited IDS
Acquired
TTR gene variants (V122I; I68L;
L111M; T60A; S23N; P24S; W41L;
V30M; V20I), APOA1
HOGA1 (type 3)
SLC40A1, TfR2
FLNC, LDB3, MYOT
TNNC1, DES, MYH, MYL3, CRYAB
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
Table 9.3 Clinical prole and relevant association
Previous malignancy Metastatic tumors, lymphoma, multiple myeloma, postradiation
therapy
Drug history Anthracycline, doxorubicin, antimalarial agents, L -tryptophan,
busulfan, mercurial agents
Weight loss Amyloidosis, neuromuscular disorders
Renal dysfunction Cystinosis, scleroderma, mitochondrial myopathy, amyloidosis,
Fabry disease
Gastrointestinal
involvement
Lung involvement Scleroderma, carcinoid, Churg-Strauss syndrome
Flushing Carcinoid
Allergic rhinitis and nasal
polyps
Diabetes mellitus Hemochromatosis, mitochondrial myopathy
Hepatic dysfunction Hemochromatosis, amyloidosis
Acroparesthesias Fabry disease
Bone pain Multiple myeloma
Fever Reactive arthritis
Source: Adapted from Stollberger etal. Extra-cardiac medical and neuromuscular implications in
restrictive cardiomyopathy [228]
Table 9.4 Blood investigations and aetiology of restrictive cardiomyopathy
Peripheral blood
eosinophilia
Anemia and
thrombocytopenia
Raise hepatic enzymes,
renal dysfunction
Elevated serum muscle
enzyme levels
Serum and urine protein
electrophoresis
Hypothyroidism Mitochondrial myopathy, POEMS syndrome, cystinosis
Raised plasma brain-
natriuretic peptide5
Scleroderma, mitochondrial myopathy, carcinoid, amyloidosis
Churg-Strauss syndrome
Hypereosinophilic syndrome, Churg-Strauss syndrome
Gaucher’s disease
Storage disorders, hemochromatosis, amyloidosis
Neuromuscular disorder
Gammapathies-Amyloidosis, POEMS (polyneuropathy,
organomegaly, endocrinopathy, M-protein, skin changes)
syndrome, Fabry’s disease
To differentiate restrictive cardiomyopathy from constrictive
pericarditis
v. Biventricular hypertrophy
vi. Obliquely elevated ST-T segments (indicating abnormal diastolic relaxation
and ventricular repolarization abnormalities)
vii. ST segment depression and T wave inversion
viii. Late peaked T wave, matched biphasic T waves due to abnormal
repolarization
ix. Prolonged QT interval
9.5 Restrictive Cardiomyopathy
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x. Heart block, atrioventricular block, bundle branch block, intraventricular con-
duction delay
xi. Junctional bradycardia, sinus nodal dysfunction
xii. Tachycardia-bradycardia syndrome
• Biopsy from skin, liver, muscle, iron prole, Positron-emission tomography, and
genetic analysis to diagnose autosomal dominant mutations, such as Noonan
syndrome; variants of skeletal myopathies and autosomal recessive mutations
associated with restrictive cardiomyopathy and muscle skeletal abnormalities [226].
9.5.4.2 Echocardiography
The common echocardiographic ndings of cardiac amyloidosis are biatrial dilation, normal or undersized ventricles, preserved left ventricular systolic function,
and mild-to-moderate mitral and/or tricuspid regurgitation,moderate-to-severe pulmonary artery hypertension,.concentric thickening of left ventricular wall and septum, right ventricular free wall and interatrial septum, thickened valves, pericardial
effusion, and characteristic sparkling appearance of the myocardium.
The transmitral Doppler spectrum shows a high E-wave with a shortened deceleration time <150 ms and E/A ratio of >2.6. In chronic constrictive pericarditis,
there is greater than 25% respiratory variation in transmitral ow velocity and transtricuspid ow velocity, whereas no such respiratory variation is seen in restrictive
cardiomyopathy. Unlike chronic constrictive pericarditis, the tissue annular Doppler
velocities are reduced in restrictive cardiomyopathy. The pericardial thickness is
increased in chronic constrictive pericarditis, but not in restrictive cardiomyopathy
(Table9.1). The inferior cava may be dilated in both entities. In cardiac amyloidosis, global longitudinal strain is typically more impaired in basal and middle segments than at apex.
9.5.4.3 Hemodynamics
The lling pressures are increased in most patients with restrictive cardiomyopathy.
The left ventricle is more affected than the right ventricle. Therefore, the rise in left
ventricular end-diastolic pressure is more than the right.
Pulmonary artery wedge pressure tracing reveals giant V-waves because of poor
atrial compliance. The square root sign is seen in 43% of patients with restrictive
cardiomyopathy, even though it is classically described for chronic constrictive
pericarditis. The haemodynamic differences between chronic constrictive pericarditis and restrictive cardiomyopathy are tabulated in Table9.1.
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9.5.4.4 Endomyocardial Biopsy
Endomyocardial and renal biopsy may be useful in arriving at a conrmatory diagnosis of amyloidosis. Muscle biopsy is useful to diagnose musculoskeletal disorders. Liver biopsy can help diagnosing glycogen and lysosomal storage disorders.
9.5.5 Treatment
The diagnosis of restrictive cardiomyopathy requires a high index of suspicion.
Earlier the diagnosis is conrmed, better the prognosis. Treatment differs according
to the underlying aetiology and includes heart failure therapies, immunosuppressive
agents, device implantation, and cardiac transplantation. A pulmonary vascular
resistance of more than 6units/m2 is a contraindication for cardiac transplantation.
9.6 Sarcoidosis
9.6.1 Clinical Features andDiagnosis
The heart is involved in 2.5–5% patients with systemic sarcoidosis in clinical series
and up to 25% in autopsy series [168, 192, 245]. The histopathological hallmark of
sarcoidosis, noncaseating granulomas, involve the left ventricular myocardium,
atria, right ventricle, papillary muscles, valves, pericardium, and even coronary
arteries.
The patients with cardiac sarcoidosis most commonly present with heart failure,
but may also present with syncope, palpitations, dyspnoea, fatigue, chest pain, or
sudden cardiac death.
The diagnosis of systemic sarcoidosis with cardiac involvement is made as per
the guidelines of Japanese Ministry of Health and Welfare (JMHW) criteria and the
Heart Rhythm Society (HRS) expert consensus statement [11, 12, 129, 193, 228],
which include the presence of noncaseating granulomas on endomyocardial biopsy
and either positive extracardiac biopsy or clinical diagnosis based on major and
minor criteria.
Conduction abnormalities that are commonly seen in such patients include complete heart block, right bundle branch block, ventricular tachycardia, supraventricular arrhythmias, frequent premature ventricular contractions and ventricular
brillation.
9.6 Sarcoidosis
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9.6.2 Investigations
A 24-hour Holter monitoring is essential in a suspected case of cardiac sarcoidosis
[13, 112, 169].
Cardiac positron emission tomography (PET) imaging assesses both myocardial
perfusion and metabolism in a single session. The former assesses resting myocardial perfusion and areas of brosis using 82-Rubidium or 13N-ammonia; and the
latter images inammation using F-18-uorodeoxyglucose (FDG). In early stages
of the disease, resting perfusion defects may be seen and focal areas of increased
FDG uptake are present. In advanced stages, resting perfusion defects may be seen
and also the absence of FDG uptake, indicating the presence of non-inammatory
scars. Whole-body FDG imaging, is increasingly being performed to evaluate for
extracardiac sarcoidosis. A biopsy can also be obtained from organs showing high
metabolic activity. Hence, PET-CT is useful for diagnosis, staging, prognosis, and
guiding immunosuppressive therapy. The presence of both perfusion and metabolic
defect on baseline imaging is a strong predictor of death or ventricular tachycardia
[130–134, 246, 262]. On cardiac magnetic resonance imaging, areas of late gadolinium enhancement, usually in a subepicardial or transmural distribution, may be
identied.
The gold standard for diagnosing sarcoidosis is the identication of noncaseating
granulomas in myocardial tissue. However, because of the patchy nature of involvement, the sensitivity of endomyocardial biopsy is less than 20%. In patients with
extra-cardiac sarcoidosis, lymph node or lung biopsy is generally helpful to establish the diagnosis.
9.6.3 Treatment
Standard medical treatment for heart failure and arrhythmias is required in cardiac
cases. Immunosuppressive therapy is considered for those with active inammatory
disease and either of the following cardiac presentations: (a) high-grade atrioventricular block, (b) reduced left ventricle ejection fraction, (c) frequent premature
ventricular contractions / frequent non-sustained ventricular tachycardia, and (d)
sustained ventricular tachycardia / ventricular brillation [53, 170].
The mainstay of treatment for cardiac sarcoidosis are corticosteroids.
Antimetabolites, such as methotrexate, azathioprine, leunomide, mycophenolate
mofetil, and cyclophosphamide are used as second-line agents. If the disease progresses despite use of these drugs, tumour necrosis factor-α inhibitors such as infliximab, adalimumab or anti-CD-20 monoclonal antibody rituximab should be
considered [99, 144]. Device therapy, such as permanent pacemakers and implantable cardiac debrillators, is appropriately indicated in patients. Orthotopic cardiac
transplantation is indicated in occasional patients with intractable arrhythmias or
end-stage heart failure [44, 99, 113, 144, 277, 278].
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
9.7 Cardiac Hemochromatosis
Hereditary hemochromatosis is characterized by increased iron absorption, which
accumulates leading to organ dysfunction. Mutations of specic genes involved in
iron absorption and metabolism are the predominant causes. The most common
mutation involves the gene HFE C282Y in autosomal recessive fashion.
The clinical manifestations include fatigue, skin hyperpigmentation (bronze
skin), cardiac conduction defects, hepatopathy (hepatomegaly, hepatitis, cirrhosis,
hepatocellular carcinoma), arthralgia, endocrinopathies including diabetes mellitus,
male hypogonadism, and cardiomyopathy. These patients are also predisposed to
various infections (Vibrio vulnicus, Listeria monocytogenes, and Yersinia enterocolitica. Cardiac involvement is present in 15–20% of cases [76]. In addition to
inltration-related restrictive heart failure, there are various conduction disturbances
in the heart.
Echocardiography helps in conrming restrictive physiology in affected patients.
Cardiac MR imaging is a valuable tool to quantify heart and liver iron [114], and it
may obviate the need to perform organ biopsy. Identication of the two most common HFE gene mutations—C282Y and H63D conrms the diagnosis of hemochromatosis [15].
The treatment of choice for symptomatic patients is therapeutic phlebotomy.
Patients with cardiac dysfunction require a less aggressive phlebotomy plan with a
less frequent schedule and lower blood collection per session. Phlebotomy is generally repeated until serum ferritin falls below 50ng/mL and transferrin saturation is
<50%. Iron-chelating agents are usually not required and are poorly tolerated.
Chelation can be considered in patients in whom phlebotomy is contraindiacted due
to anaemia, hypotension or hypovolaemia [174].
The prognosis is dependent upon the presence of liver involvement, particularly
cirrhosis and hepatocellular carcinoma, and cardiac involvement.
9.8 Budd-Chiari Syndrome
9.8.1 Denition
Budd-Chiari syndrome is an unusual form of portal hypertension characterized by
hepatic venous outow tract obstruction, irrespective of the level or mechanism of
obstruction. Cardiac and pericardial diseases, and sinusoidal obstruction syndrome
occurring due to exposure to toxic substances are excluded from this denition
[5, 6, 26].
9.8 Budd-Chiari Syndrome
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9.8.2 Epidemiology
Due to the limited availability of published data, the exact prevalence of BuddChiari syndrome is unknown. This syndrome is more prevalent in northern India,
South Africa and the Orient compared to the USA [201, 229, 257, 263–265].
The literature documents different levels of obstruction according to area. Pure
inferior caval vein or combined inferior caval vein/hepatic vein block is predominant in Asia, whereas pure hepatic vein block is predominant in western countries.
Environmental factors, oral contraceptives and poor nutrition have been variously
incriminated as causative factors in some cases [57, 257, 263–265].
9.8.3 Aetiology
The Budd-Chiari syndrome may be classied as primary or secondary depending on
the cause of obstruction of hepatic veins or hepatic portion of inferior cava. In primary type, the obstruction is caused by webs, diaphragms, thrombosis, or phlebitis;
whereas in secondary type, by thrombosis, benign or malignant tumor, abscess,
cyst, or trauma [145, 180].
Obstruction of hepatic venous outow tract has been further classied depending
on the location: small hepatic veins, large hepatic veins, inferior caval vein, and
combined obstruction of large hepatic veins and inferior caval vein [125].
9.8.4 Secondary Budd-Chiari Syndrome
Hepatocellular carcinoma, primary hepatic haemangioma, epitheloid haemangioendothelioma, renal adenocarcinoma, adrenal adenocarcinoma, rhabdomyosarcoma
of inferior caval vein and alveolar hydatid disease may cause Budd-Chiari syndrome by causing invasion of hepatic venous outow [179, 257, 263–265]. Parasitic
and non-parasitic cysts, focal nodular hypoplasia, post hepatic resection, and post
hepatic transplantation may also cause compression and thrombosis of the hepatic
venous outow tract [179, 194, 253, 257, 263–265].
Blunt abdominal trauma with intrahepatic haematoma causing hepatic venous
outow obstruction, and inferior caval venous thrombosis following diaphragmatic
rupture and herniation of liver, are other causes of Budd-Chiari syndrome [15,
115, 146].
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9 Diseases Mimicking Constrictive Pericarditis: Salient Features and Novel Strategies…
9.8.5 Primary Budd-Chiari Syndrome
Myeloproliferative diseases and prothrombotic disorders (thrombophilia) account
for half of Budd-Chiari syndrome cases [16, 45, 58, 59, 89, 98–100, 116, 117, 182,
183], followed by Factor V Leiden mutation, antiphospholipid syndrome and
G20210A prothrombin gene mutation. The role of protein C, protein S and antithrombin deciency, or hyperhomocysteinemia remains unclear because of underlying liver disease. Paroxysmal nocturnal haemoglobinuria accounts for ~5% of
Budd-Chiari syndrome patients.
Behcet’s disease, hypereosinophilic syndrome, granulomatous vasculitis, pregnancy, and ulcerative colitis are additional risk factors for Budd-Chiari syndrome
[16, 195, 279, 280, 286]. Environmental risk factors consist mainly of poor standards of living in Asia and the use of oral contraceptives [98, 100, 101, 201,
257–265].
A combination of several causal factors like pregnancy, and heterozygous factor
V Leiden is demonstrated in ~25% of patients [60, 89, 98, 100]. An underlying
predilection for thrombosis is found in 87% of Budd-Chiari syndrome patients [60].
9.8.6 Clinical Manifestations
Asymptomatic Budd-Chiari syndrome accounts for 15–20% of cases [90]. The classical presentation of Budd-Chiari syndrome is with fever, abdominal pain, ascites
and pedal oedema, and less commonly with jaundice, hepatic encephalopathy and
gastrointestinal bleeding. Levels of serum albumin, serum bilirubin, and prothrombin may be abnormal; and serum transaminases and alkaline phosphatase may be
increased [181, 184].
The course of the disease can be steady, fulminant hepatic failure or a long insidious course marked by exacerbations and remissions. Portal vein obstruction occurs
commonly in severe forms of the disease. In diagnostic evaluation of acute or
chronic liver diseases, assessment of patency of inferior caval vein and hepatic veins
should be part of routine assessment.
9.8.7 Natural History
Natural history of symptomatic Budd-Chiari syndrome is universally fatal. Tavill
AS and colleagues reported 90% 3year mortality in a British cohort of Budd-Chiari
syndrome in the 1960s when no therapy was available. The causes of death were
intractable ascites, emaciation, gastrointestinal bleeding, and ultimately hepatic
failure [250].
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