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eurjpc1806
eurjpc1806
Keywords
Cardiac amyloidosis, diagnosis, red flags
Received 13 July 2019; accepted 1 September 2019
Cardiac amyloidosis: why to suspect it therapy and better support therapy for cardiac amyl-
Amyloidosis is a systemic disease characterised by oidosis (CA), patient survival is improving.3
extracellular deposition of insoluble fibrils, deriving TTR is a highly conserved protein rich in beta strands
from proteins encoded by mutated genes or normal, which is synthesised mostly by the liver and involved in
misfolded proteins. Cardiac involvement in amyloid- the transportation of thyroxine and retinol-binding pro-
osis is a major determinant of clinical presentation tein. Wild-type (wt) TTR has an intrinsic propensity to
and outcome, and is common in immunoglobulin aggregate into insoluble amyloid fibres. The process of
light-chain (AL) amyloidosis and transthyretin amyl- fibrillogenesis requires the dissociation of TTR
oidosis (ATTR).
AL amyloidosis is the most common type of sys- 1
Institute of Life Sciences, Scuola Superiore Sant’Anna, Italy
temic amyloidosis, affecting approximately 10 people 2
Fondazione Toscana Gabriele Monasterio, Pisa, Italy
per million per year.1 Monoclonal light chains undergo 3
Department of Clinical and Experimental Medicine, University of Pisa,
extracellular misfolding and aggregation into proteo- Italy
toxic soluble oligomers and, finally, into amyloid fibrils.
Corresponding author:
The outcome of patients with AL amyloidosis is poor, Giuseppe Vergaro, Scuola Superiore Sant’Anna and Fondazione Toscana
especially when cardiac involvement is present.2 Gabriele Monasterio, Via G. Moruzzi 1, 56124 Pisa, Italy.
Nonetheless, given recent advances in haematological Email: vergaro@ftgm.it
Vergaro et al. 1807
homotetrameric structure into misfolded monomers observed in advanced stages of disease, while cardiac
that self-assemble in soluble oligomeric species, protofi- involvement may be more subtle or even asymptomatic
brils and finally mature amyloid fibres, which deposit in earlier phases.13
within tissues. ATTR can follow the deposition of AL amyloidosis is a systemic disease, with half of the
either mutant (variant ATTR, vATTR) or wild-type patients having renal involvement, 16% having liver
TTR (ATTRwt). Single-base substitutions resulting in disease and 10% having neuropathy.14 Information
missense mutations represent the majority of genetic about the coexistence of such conditions should be
alterations in vATTR; the clinical presentation of acquired as a part of routine patient interview.
vATTR is largely influenced by the underlying muta- Phenotypic heterogeneity is also significant in the case
tions, ranging from pure polyneuropathy (as in familial of vATTR, following differences in the responsible
amyloid polyneuropathy), to the coexistence of neuro- mutation, penetrance, ethnicity and geographical area.
logical and cardiac disease, to isolated cardiomyopathy. Some mutations are associated with combined neuro-
nNT-proBNP
Restrictive Bilateral CTS /BNP
Abnormal
CMP Histology liver
Popeye Sign function
HFmr/pEF
Periorbital purpura
Genetic testing n troponin
CARDIAC
AMILOIDOSIS
Mass/
voltage Diffuse
AV
discrepancy subendocardial LGE
conduction
Early darkening Pleural
disorders RV
Low QRS Cardiac uptake effusion
dysfunction
voltages with bone tracers
Apical
LBBB/ sparing
RBBB Increased wall
Pseudonecrosis Pericardial
thickness
ECG Q waves effusion IMAGING
Supraventricular
Atrial dilation/
arrhythmias
dysfunction
Figure 1. Clinical, electrocardiographic, biohumoral and imaging findings raising the suspicion of cardiac amyloidosis. Darker areas
indicate higher diagnostic specificity. AV: atrio-ventricular; BNP: B-type natriuretic peptide; CMP: cardiomyopathy; CTS: carpal tunnel
syndrome; GFR: glomerular filtration rate; HFmr/pEF: heart failure with mid-range/preserved ejection fraction; LGE: late gadolinium
enhancement; NT-proBNP: N-terminal fraction of B-type natriuretic peptide; RV: right ventricular.
pericardial or pleural effusion, obesity, emphysema, by echocardiography could be even more relevant than
pneumothorax, or myxoedema.19,20 Among 337 QRS voltages per se.
consecutive treatment-naive AL amyloidosis patients Conduction disturbances are also common in
(233 with cardiomyopathy and 104 without), the esti- patients with CA. Among 344 patients diagnosed with
mated prevalence of low-voltage patterns in AL amyl- AL amyloidosis, those with cardiac involvement
oidosis ranged from 84% when the Sokolow–Lyon (n ¼ 240) displayed prolonged PQ, QRS, QT and QTc
index of 15 mm or less was used as a cut-off, to 27% intervals (all P < 0.05) and a higher prevalence of intra-
when low voltages were defined as QRS amplitude of ventricular blocks (28% vs. 17%, P < 0.05).22 Other
5 mm or less in each peripheral and 10 mm or less in ECG features described in patients with AL-type CA
each precordial lead.21 In other cohort studies on AL are a pseudo-infarction pattern with QS complexes in
amyloidosis, using different diagnostic criteria, the the anterior leads, an unusual axis of the QRS complex
prevalence of low QRS voltages ranged from 42% to (particularly extreme right axis deviation),19 abnormal
71%.18–21 Finally, among patients with biopsy-con- P wave morphology and duration (reflecting slow atrial
firmed CA, only 60% (AL) and 35% (ATTR) displayed conduction). In AL-type CA, a fragmentation of QRS
low peripheral voltages (<5 mV in all peripheral complexes has been reported, consisting of abnormal-
leads).18 Overall, despite the multiplicity of diagnostic ities such as notches and a RsR0 pattern in the absence
criteria, the absence of a low-voltage ECG pattern of QRS prolongation, reasonably due to areas of
does not rule out AL or ATTR-type CA and the discrep- myocardial necrosis and fibrosis.23 Atrial fibrillation
ancy between QRS voltages and LV mass as measured is also rather frequent in patients with amyloidosis.
Vergaro et al. 1809
For example, more than half of patients with ATTRwt diagnosis and risk stratification in both acute and
had any form of atrial fibrillation in a recently pub- chronic settings, as in HF and cardiomyopathies. The
lished series.13 elevation of plasma highly sensitive troponin T (hs-
TnT) is observed in the vast majority of patients with
AL amyloidosis, including those free from overt cardiac
Laboratory findings
involvement, and represents a red flag for the disease.
Sensitive biomarkers are required to identify cardiac Moreover, hs-TnT is associated with clinical indices of
damage at an early, asymptomatic stage. Such markers HF severity, LV systolic dysfunction, and wall thick-
might be particularly useful in patients considered at ness in patients with AL-type CA.30 The exact mechan-
higher risk for the development of amyloidosis, such ism of cTn release in patients with amyloidosis has to
as those with monoclonal gammopathy of unknown be elucidated, but the proinflammatory or toxic effects
significance (MGUS), at risk of AL CA especially of the amyloid fibres or their precursors and/or micro-
the disease progression, which helps differentiate CA pattern of ventricular remodelling in ATTR-type CA
from disorders such as constrictive pericarditis or (79%), followed by symmetrical concentric hypertro-
HCM, in which E0 is normal or mildly reduced.34 phy (18%) and the absence of LV hypertrophy (3%).
Strain imaging demonstrates an impairment of lon- Asymmetrical hypertrophy was much less frequent in
gitudinal ventricular contraction before the decline of AL amyloidosis (14%), while concentric hypertrophy
ejection fraction and HF development. In a study of was found in 68%, and no hypertrophy in 18%.43
40 patients with biopsy-confirmed CA and 60 patients Hypertrophy is typically more pronounced than in
with HCM or hypertensive heart disease, LV global hypertensive or valvular heart disease, and is more
longitudinal strain (GLS) showed the best performance prominent in ATTR than AL amyloidosis.42 Contrary
to discriminate CA, both in the whole population and to HCM or other forms of secondary hypertrophy,
in the subgroups with maximum wall thickness of changes over months in wall thickness and function
16 mm or less or left ventricular ejection fraction are quite typical of AL amyloidosis.42 The LVEF may
AL-type CA), and allow us to differentiate with high terms of septal thickness or impaired longitudinal func-
accuracy AL and ATTR cardiomyopathy from tion, provides the conceptual framework for the visual
HCM.42 An increase in native T1 may represent a red Perugini scoring system: grade 0, no cardiac uptake;
flag for the disease, as it is observed before the onset of grade 1, cardiac uptake present but less intense than
LV pseudohypertrophy, LGE development or elevation the bone signal; grade 2, cardiac uptake with intensity
in blood biomarkers, and is also able to track cardiac similar to or greater than bone signal; grade 3, cardiac
amyloid burden with the potential to become a useful uptake with much attenuated or absent bone signal.52
tool to quantify cardiac amyloid and track changes This system has been incorporated in the algorithm for
over time.42 At 1.5 T, specific native myocardial T1 the non-biopsy diagnosis of ATTR-type CA, in which
cut-off values have been found (<1036 ms to exclude diphosphonate scintigraphy is advised when CA is sus-
CA with 98% negative predictive value; T1 > 1164 ms pected based on a combination of clinical, biohumoral
to confirm CA with 98% positive predictive value), and and/or imaging data. When the Perugini grade is 2 or 3,
RED FLAGS
>LV wall thickness + low QRS voltage, +/– HF symptoms,
<troponin/B-type natriuretic peptides, peripheral/autonomic neuropathy,
family history, multi-organ involvement
Figure 2. Diagnostic algorithm for cardiac amyloidosis. A schematic representation of the diagnostic algorithm for cardiac amyl-
oidosis, revised from that proposed by Gillmore et al.,41 is proposed. Consultation with a haematologist is warranted when a
monoclonal component is detected. AL: immunoglobulin light-chain amyloidosis; ATTR: transthyretin amyloidosis (ATTRv): variant
transthyretin amyloidosis; ATTRwt: wild-type transthyretin amyloidosis; CMR: cardiac magnetic resonance; HF: heart failure. Modified
from Emdin et al.9
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