Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3099_Библиотеки_им_академика_М_И_Перельмана.pdf
Amyloid Cardiomyopathy
7
of amyloid deposition is most often performed by an indirect
immunohistochemical method and direct immunofluorescence. Both methods
are based on the principle of reaction of an antibody with an antigen –
amyloidogenic protein epitope (light chains, transthyretin, SAA) with a
standard visualization by the avidin-biotin complex technique on slices of
formaldehyde-fixed tissue cast in paraffin blocks. In case of
immunofluorescence, native, frozen non-fixed tissue is used, and the
antibodies are tagged with a fluorochrome [26 – 29]. Presently, many centers
use advanced techniques for the visualization and determination of amyloid
mass type, including electron microscopy or mass spectroscopy techniques
[30, 31]. Provided that amyloid from non-targeted or extracardial biopsy is
verified in case of AL amyloidosis, endomyocardial biopsy is not necessary
for verification of amyloid cardiomyopathy diagnosis. Consensus of the 10th
ISA symposium in Tours (2004) established that amyloid cardiomyopathy is
proven in case of echocardiographically verified end-diastolic interventricular
septum thickness of > 12 mm in the absence of other possible hypertrophy
cause (e.g., arterial hypertension) [32]. Endomyocardial biopsy is indicated in
case of significant suspicion of amyloid cardiomyopathy and negative
extracardiac biopsies, in case of mTTR amyloidosis with Val122Ile mutation
and dominant cardiac involvement, prior to heart transplantation and in the
post-transplantation period for the detection of rejection episodes, in case of
uncertain states – for example with concurrent intractable hypertension, or in
case of narrower interventricular septum [10]. Genetic analysis of the TTR
gene is necessary for the confirmation of mTTR or exclusion of SAA.
CARDIAC BIOMARKERS
Cardiac biomarker assay is a necessary part of the diagnostic algorithm for
AL amyloidosis patients. Troponin T (TnT), troponin I (TnI) and N-terminal
pro-brain natriuretic peptide (NT-proBNP) levels are usually tested by
standardized laboratory methods. TnT levels are a sensitive indicator of
myocardial involvement, and the levels determined at the time of diagnosis are
used as a prognostic parameter (levels > 0.035 µg/L). TnT (TnI) levels, aside
of their prognostic significance, are presently used along with NT-proBNP
levels as discrimination parameters in a rather widely used staging system
published by a Mayo Clinic group, which enables not only a stratification of
Tomas Pika and Jiri Vymetal
8
patients into 3 risk groups, but also permits to a certain degree the
determination of adequate therapy (Stage I: TnT < 0.035 μg/L (TnI < 0.1 μg/L)
and NT-proBNP < 332 ng/L (OS 26.4 m), Stage II: TnT > 0.035 μg/L (TnI >
0.1 μg/L) or NT-proBNP > 332 ng/L (OS 10.5 m), Stage III: TnT > 0.035 μg/L
(TnI > 0.1 μg/L) and NT-proBNP > 332 ng/L (OS 3.5 m)). At present, this
stratification system has been further modified and supplemented with the
parameter of free light chain level assay representing the amyloidogenic
protein burden. Troponin levels correlate with LVEF value and
interventricular septum thickness; likewise, the effect of a
chemo(immuno)therapy is associated with the decrease of these levels. It is
known that steady or increasing troponin levels indicate continuing loss of
cardiomyocytes. An overestimation of troponin levels in case of renal
insufficiency represents a limit to the assay [33 – 38].
Serum NT-proBNP assay is nowadays commonly used in the care of
patients with cardiac involvement. Analogous to those of troponin, NT-
proBNP levels enable prognostic stratification of AL amyloidosis patients (>
332 ng/L), while normal levels practically rule out amyloid cardiomyopathy.
Elevation of NT-proBNP levels is an early marker of cardiac involvement in
amyloidosis, but it is necessary to point out that elevation of the levels often
does not correspond with the degree of cardiac dysfunction. The NT-proBNP
assay is currently used as a part of the above mentioned Mayo Clinic
stratification system [34, 39, 40]. NT-proBNP levels > 8500 ng/L along with
systolic pressure values < 100 mmHg also identify patients at high risk of
early death [41]. The change of NT-proBNP levels correlates with the
dynamics of free light chain levels, i.e., circulating amyloidogenic precursors,
and also with the improvement of echocardiographic finding following a
successful therapy; this indicator appears to be a plausible supplemental
parameter for therapy optimization. A study published by Palladini et al.
applied the change of NT-proBNP by 30% and at least 300 ng/L as the
criterion for treatment response or disease progression. Effective therapy is
associated with the decrease of absolute values; presently, change of NT-
proBNP levels is being used as a criterion for the evaluation of cardiologic
remission [42]. B-type natriuretic peptide (BNP) assay presents an advantage
for these patients, because an overestimation of troponin levels in case of renal
insufficiency represents a limit to the NT-proBNP assay [43]. Lasting elevated
NT-proBNP levels are also characteristic for immune modulation therapy
(lenalidomide), while the mechanism of this phenomenon is still not fully
elucidated [44].
Amyloid Cardiomyopathy
9
Table 2. Cardiac response and progression criteria [42]
Response
NT-proBNP
> 30% and >300 ng/L decrease if baseline NT-proBNP
≥ 650 ng/L
NYHA
≥ two-class decrease if baseline NYHA class 3 or 4
Progression
NT-proBNP
> 30% and > 300 ng/L increase
Troponin
≥ 33% increase
LVEF
≥ 10% decrease
Abbreviations: NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New
York Heart Association; LVEF, ejection fraction of left ventricle.
ELECTROCARDIOGRAPHY
Electrocardiography (ECG) is one of the basic examination methods in the
daily clinical practice of an internist or cardiologist. Low amplitude of the
QRS complex < 0.5 mV in the extremity leads and/or < 1.0 mV in the
precordial leads represents a finding typical for amyloid cardiomyopathy. This
finding is present in approximately 2 out of 3 patients with AL amyloidosis.
Unlike hypertrophic cardiomyopathy, which is caused by hypertrophy of
cardiomyocytes, the cause of cardiac wall hypertrophy in amyloid
cardiomyopathy is the imbibition of walls with amyloid associated with
myocyte loss [45 – 47]. Therefore a finding of reduced ECG voltage and
myocardial hypertrophy in echocardiographic examination may be indicative
of the possibility of amyloid cardiomyopathy [48]. A QS pattern in at least two
adjacent precordial chest leads (“a pseudo-infarct pattern”) and an inversion of
T-waves or ST-segment depression in the lateral chest leads counts among
other findings in some of the patients [45 – 47]. A majority of patients with
SSA usually does not present the above mentioned ECG signs, but they show
frequent findings of left bundle branch block and supraventricular arrhythmia
(fibrillation, atrial flutter). AL amyloidosis patients, on the other hand,
frequently register sinus rhythm [9, 49]. Holter ECG shows attacks of
ventricular and supraventricular arrhythmias in a large portion of
asymptomatic patients; another finding is the decrease or absence of cardiac
frequency variability, which is a sign of autonomous nervous system
dysfunction [50 – 52].
Tomas Pika and Jiri Vymetal
10
Figure 1. ECG of an amyloidosis patient. Reduced voltage in the extremity leads, QS
in the anterior chest leads (“pseudoinfarct pattern”).
ECHOCARDIOGRAPHY
Because of its availability, transthoracic echocardiography represents an
imaging method of first choice for the diagnostics and monitoring of cardiac
involvement in amyloidosis. It is necessary to state that characteristic findings
are usually discernible only in later stages of the disease, and that
echocardiography per se cannot confirm the diagnosis of amyloidosis, nor can
it distinguish among its individual types [53]. A finding typical for infiltrative
affection of the myocardium is end-diastolic thickness of the interventricular
septum or left ventricular wall > 12 mm; wall thickness > 15 mm is associated
with significantly worse prognosis [54]. The use of the term “hypertrophy” is
not in this case entirely correct from the viewpoint of pathogenesis, as the
condition is not caused by the hypertrophy of cardiomyocytes, but by amyloid
deposition. Nevertheless, the finding of “concentric hypertrophy” of the left
ventricle in a routine echocardiography in the absence of hypertension or
another cause explaining myocardial hypertrophy should lead to a
consideration of the presence of amyloidosis. Infiltration of the myocardium
with amyloid should be indicated also by a “granular sparkling” texture, as the
amyloid deposits exhibit a higher echogenicity than a normal myocardium; the
current use of harmonic frequencies that generally increase the myocardial
echogenicity, however, make this perception largely subjective. The left
Amyloid Cardiomyopathy
11
ventricle is not dilated; on the contrary, the left ventricular cavity is reduced in
case of prominent involvement. LVEF as a global parameter is preserved
particularly in early stages (LVEF > 50%), but a dominant disorder of
longitudinal contractility typical for amyloidosis, particularly of the basal
segments of the left ventricle, can be demonstrated sooner in an examination
with tissue Doppler (S and Em wave reduction of the septal and lateral edge of
the mitral annulus) or in the evaluation of longitudinal strain of the left
ventricle by speckle tracking echocardiography [15, 55]. There are regular
findings of diastolic dysfunction of the left ventricle, from a mild diastolic
relaxation disturbance to the image of a severe restrictive disorder (E/A ratio >
2) with high left ventricular filling pressures (elevated E/Em ratio), and atrial
dilatation in later stages (diameter > 23 mm/m
2
, area > 20 cm
2
or maximal
volume > 28 mL/m
2
, small A wave due to atrial dysfunction) [56, 57].
Thickening of the free right ventricular wall and its dysfunction, as well as
thickening of the valves, also indicates that these structures were damaged by
amyloid. Pericardial effusion is present in about 50% of the patients. It is
usually small and of little hemodynamic significance, but is associated with
worse prognosis; large effusion with the possibility of a tamponade is found
only exceptionally [58].
(a)
Figure 2. (Continued)
Tomas Pika and Jiri Vymetal
12
(b)
(c)
Figure 2. Transthoracic echocardiography. Parasternal long axis (PLAX) view (a) and
apical four chamber (A4C) view in diastole (b) and in systole (c). Apparent prominent
thickening of the left ventricular myocardium (24 mm) with amyloid deposits,
insignificant pericardial effusion discernible in PLAX. A patient with implanted ICD,
right ventricular lead visible in A4C (c).
SCINTIGRAPHY
Some centers use radiolabelled serum amyloid P component (SAP) to
visualize the whole body amyloid burden. SAP forms a part of all amyloid
Amyloid Cardiomyopathy
13
deposits, regardless of amyloidogenic protein type. The method is used for the
assessment of distribution and degree of involvement, as well as for
monitoring of treatment response. Nevertheless, the method is not suitable for
myocardial visualization because of the distribution of the radiopharmaceutical
in the blood compartment of the moving heart and frequent accumulation in
the spleen, located in the vicinity of the heart [59, 60]. Some centers presently
use
99m
Tc-3,3-diphosphono-1-2-propanodicarboxylic acid (DPD) scintigraphy.
99m
Tc-DPD is selectively taken up in the myocardium with TTR amyloid
deposits, which is advantageous not only for the diagnostics and assessment of
heart involvement in mTTR and SSA, but also for the differential diagnostics
of AL, where the accumulation of the radiopharmaceutical is very low or
absent [61 – 63]. Scintigraphy using
99m
Tc-aprotinin appears beneficial for the
evaluation of cardiac involvement, but practical experience is limited so far
[64, 65].
Figure 3.
99m
Tc-DPD scintigraphy in ATTR amyloidosis. Whole-body image with
diffusely increased radiopharmaceutical uptake in the myocardium in the anterior and
posterior projection. (Courtesy of prof. M. Kaminek M.D., Department of Nuclear
Medicine, Olomouc University Hospital).
Tomas Pika and Jiri Vymetal
14
MAGNETIC RESONANCE
Magnetic resonance imaging (MRI) of the heart enables a more accurate
morphological and functional imaging of the heart compared to
echocardiography, and its use is presently on the rise. The findings are the
same as with echocardiography: hypertrophy of ventricular walls and septum,
atrial dilatation and hypertrophy, preserved or reduced ejection fraction of a
non-dilated left ventricle with decreased longitudinal contraction of the walls;
pericardial effusion is often present. Contrast examination by the late
gadolinium enhancement (LGE) method represents a great contribution to the
evaluation of amyloid cardiomyopathy. The morphological grounds of LGE
has not been elucidated so far; expansion of the interstitium due to amyloid
infiltration or interstitial fibrosis, which extend gadolinium deposition in the
tissues, is being considered [66 – 68]. Amyloid cardiomyopathy most often
presents the finding of global subendocardial LGE; homogeneous or
heterogeneous transmural LGE is less frequent. These findings are typical and
pathognomonic for amyloid cardiomyopathy, have high sensitivity and
specificity, and can be found in 80% of patients [69, 70]. The possibility of
amyloid cardiomyopathy must be considered also in case of difficult
determination of an optimal inversion time in T1 – suboptimal “nulling” of the
hypertrophic myocardium (suppressed myocardial signal) [70]. Currently
studied native T1 mapping technique allows to assess the extent of expansion
of extracellular compartment of the imbibition amyloid, preferably earlier
detection and quantification of amyloid load [71, 72]. Application of MRI for
early diagnostics as well as for patient monitoring requires further studies.
(a)
Figure 4. (Continued)
Amyloid Cardiomyopathy
15
(b)
(c)
Figure 4. Magnetic resonance of the heart. Late-enhancement examination 10 minutes
after the application of gadolinium. Image along the short axis (a), and in two-chamber
(b) and four-chamber (c) view. Apparent global subendocardiac saturation of the left
ventricular myocardium; changes are transmural in the lateral wall. (Courtesy of Z.
Tüdös M.D., Department of Radiology, Olomouc University Hospital).
AL AMYLOIDOSIS THERAPY
The principle of a successful AL amyloidosis therapy is rapid elimination
of clonal plasmocytes in the bone marrow or other B-lymphocyte clonal
population responsible for the production of amyloidogenic monoclonal light
immunoglobulin chains. Only a prominent reduction of light chain burden and
Tomas Pika and Jiri Vymetal
16
obtaining at least a very good hematological response (VGPR, difference
between involved and uninvolved FLC < 40 mg/L) makes possible the
elimination of deposited amyloid masses from the organs and thus
accomplishing organ treatment response [42]. A risk-adapted approach is
currently preferred in AL with individual therapeutic strategy for each patient
with regard to age, comorbidities, and the number and degree of involvement
of individual organs. It is known that patients with advanced cardiac
involvement have a very unfavorable prognosis. A study of Wechalekar et al.,
evaluating a set of 346 AL patients in Mayo III stage, showed overall median
survival of only 7 months. The study also confirmed that a deep hematological
therapeutic response is associated with an increased rate of organ responses
and a longer patient survival [41].
Autologous stem cell transplantation, i.e., high-dose melphalan therapy
with autologous graft support (ASCT), which can be preceded by a 3–5
months induction therapy, represents so far the most effective therapeutic
modality for AL amyloidosis patients. This therapeutic modality is associated
with a high percentage of achieved remissions, but it can be offered only to
about 20% of patients owing to old age, organ involvement and other
comorbidities [73 – 75]. Currently accepted indication limits, where the
presence of a single criterion contraindicates the patient for a high-dose
therapy, are as follows: age > 70 years, performance status > 2, LVEF < 45%,
troponin value T ≥ 0.06 μg/L, NT-proBNP > 5000 ng/L, serum creatinine level
≥ 1.7 mg/dL, CO lung diffusion capacity < 50%, systolic pressure at the
forearm < 90 mmHg and a significant involvement of more than two organs
including the heart [23]. Despite these selection criteria, ASCT should be
performed at centers experienced in transplantation therapy of AL amyloidosis
patients. Growth factor administration during graft collection for the
autologous transplantation may be accompanied by aggravated congestive
heart failure or deepened hypotension, and the transfer of stem cells itself may
be associated with ventricular arrhythmias due to the toxic effect of the
cryoprotective dimethyl sulfoxide [76 – 78]. Risk-adapted ASCT is associated
with attaining hematological response in more than 70% of patients (36 - 56%
of complete remissions) with a 4, 4 – 11,5% risk of peritransplantation
mortality [79 – 81].
The standard of care for patients contraindicated for high-dose therapy is
the administration of conventional therapy – a combination of melphalan with
dexamethasone (MDex). This treatment achieves complete hematological
remission in approximately 30% of patients with a relatively good therapy
tolerance. The treatment of patients with advanced cardiac failure is