nihms855616

HHS Public Access
Author manuscript
Circulation. Author manuscript; available in PMC 2018 April 04.
Author Manuscript
Published in final edited form as:

Circulation. 2017 April 04; 135(14): 1357–1377. doi:10.1161/CIRCULATIONAHA.116.024438.
Addressing Common Questions Encountered in the Diagnosis

and Management of Cardiac Amyloidosis
Mathew S. Maurer, MD1, Perry Elliott, FRCP(UK)2, Raymond Comenzo, MD3, Marc
Semigran, MD4, and Claudio Rapezzi, MD5
1Columbia University Medical Center
2University College London & St. Bartholomew’s Hospital
Author Manuscript
3Tufts Medical Center

4Massachusetts General Hospital, Harvard University
5University of Bologna
Abstract
Advances in cardiac imaging have resulted in greater recognition of cardiac amyloidosis (CA) in
everyday clinical practice, but the diagnosis continues to be made in patients with late stage
disease, suggesting that more needs to be done to improve awareness of its clinical manifestations
and the potential of therapeutic intervention to improve prognosis. Light chain CA (AL-CA) in
particular, if recognized early and treated with targeted plasma cell therapy, can be managed very
Author Manuscript
effectively. For patients with transthyretin amyloidosis, there are numerous therapies that are
currently in late phase clinical trials. In this review we address common questions encountered in
clinical practice regarding etiology, clinical presentation, diagnosis and management of cardiac
amyloidosis, focusing on recent important developments in cardiac imaging and biochemical
diagnosis. The aim is to show how a systematic approach to the evaluation of suspected CA can
impact the prognosis of patients in the modern era.
Keywords
cardiac amyloidosis; transthyretin; light chain
Author Manuscript
Corresponding Author: Mathew S. Maurer, Columbia University Medical Center, New York Presbyterian Hospital, Clinical
Cardiovascular Research Laboratory for the Elderly, 5141 Broadway, 3 Field West, Room 035, New York, N.Y. 10034, Phone:
212-30-9808, Fax: 212-932-4538, [email protected].
Disclosures: Dr. Maurer’s institution, receives funding for research and serving on advisory boards and DSMBs from Pfizer Inc.,
Alnylam Pharmaceuticals Inc., ISIS Pharmaceuticals and Prothena Inc. Dr. Elliott reports Consultancies with Pfizer, Sanofi, Shire and
Amicus. Dr. Comenzo reports being a scientific advisor to Takeda, Prothena, Janssen and Unum. Dr. Semigran has received research
funding from Alnylam. Dr. Rapezzi has received research grants from Pfizer.
Maurer et al. Page 2
Introduction
Author Manuscript
What is amyloidosis?
Amyloidosis is a localized or systemic deposition disease in which proteins with unstable
tertiary structures misfold, aggregate and form amyloid fibrils that deposit with a range of
chaperone proteins in the heart, kidneys, liver, gastrointestinal tract, lungs and soft tissues1.
Individual amyloid fibrils are non-branching, 7 to 10 nm in width and of variable length.
They are insoluble and notably resistant to proteolysis2. The term “lardaceous disease” was
first used to describe such deposits at autopsy but was replaced by the botanical term
“amyloid” because of their starch-like affinity for iodine3. In polarized light under the
microscope, the deposits, when stained with the dye Congo red, display apple-green
birefringence, changing from a hyaline pink appearance in normal light4. Under electron
microscopy amyloid fibrils appear as needle-like structures with multiple filaments that have
a unique highly organized cross β-pleated-sheet configuration5. Among the signature
Author Manuscript
chaperone proteins found in all amyloid deposits are the pentraxin serum amyloid P
component (SAP), clusterin, vimentin, vitronectin, glycosaminoglycans and
apolipoproteins6.
What forms of amyloidosis affect the heart?

There are more than thirty proteins that can form amyloid fibrils, five of which frequently
infiltrate the heart and cause CA: immunoglobulin light chain (AL or primary amyloidosis),
immunoglobulin heavy chain (AH), transthyretin (ATTR), serum amyloid A (AA), and
apolipoprotein A I (AApoA1). The overwhelming majority of patients with CA are affected
by either AL or ATTR CA. While the general mechanism of extracellular deposition of
fibrillary proteins leading to tissue and organ dysfunction is common to all forms of CA,
Author Manuscript
there are three major precursor proteins causing CA, each with differing natural histories and
therapies including AL and ATTR due to a mutation (ATTRm) or wild type (ATTRwt).7
Epidemiology and Delays in Diagnosis

Is cardiac amyloidosis rare?
AL-CA is a rare condition with an estimated prevalence of 8 to 12 per million8–10. There are
~3,000 newly diagnosed cases of AL amyloid per year in the United States (US) of which
30–50% of which have symptomatic cardiac involvement and 10–15% occur in association
with multiple myeloma11. There are currently ~10,000 individuals affected with AL in the
US, consistent with the definition of an orphan disease as one that affects less than 200,000
persons. The population prevalence of ATTR-CA is less certain, but recent data suggest that
it is overlooked as a cause of common cardiovascular conditions in older people including
Author Manuscript
heart failure with preserved ejection fraction (HFpEF), low flow aortic stenosis and atrial
fibrillation12, 13. Autopsy data has demonstrated that among adults more than 80 years of
age, 25% have transthyretin amyloid deposits in the myocardium14. Among patients with
HFpEF, autopsy data reveal amyloid deposits in 32% of those over 75 years of age compared
with 8% of those aged <75 years (8%)15, 16. Emerging data using nuclear scintigraphy has
suggested that 13% (95% CI 7.2–19.5%) of patients hospitalized with HFpEF may have
ATTRwt-CA17. Some patients, however, have disease caused by mutations in the TTR gene

and although these are relatively rare, some genetic forms are endemic in particular
Author Manuscript
geographic regions. The Val122Ile mutation, which almost exclusively affects individuals of
African or Afro-Caribbean descent, has a population prevalence of 3–4%18 and while
clinical penetrance of this variant is incomplete in subjects up to 80 years of age, it is almost
certainly under-recognized as a cause of heart failure19. Emerging data suggest that ATTR-
CA, especially due to ATTRwt, is not uncommon and will become the most commonly
diagnosed form of CA.
How often is the diagnosis missed or delayed?

CA is often misdiagnosed and the delayed diagnosis has significant consequences for
patients. In a survey of more than 500 patients with AL (37% of whom had cardiac
involvement) the average time from initial symptoms to diagnosis was 2 years. A substantial
proportion of patients (31.8%) reported seeing at least 5 physicians before receiving a
Author Manuscript
diagnosis of amyloidosis. Cardiologists were consulted more often than hematologists,

oncologists or nephrologists, but were responsible for making the diagnosis in only 18.7% of
cases. Similar data for ATTR-CA, albeit in much smaller populations, reveals that less than
half of subjects were diagnosed within 6 months, mainly by cardiologists.20
What are the impediments to early and accurate diagnosis?

CA is a “great pretender”, often misdiagnosed as another condition or delayed in its
recognition as a result of both physician and disease related factors. Optimum diagnosis and
care requires multidisciplinary management (cardiology, neurology, nephrology and
hematology) but amyloidosis teams are relatively few. Additionally, the absence of disease
modifying therapies for ATTR and the late presentation of AL-CA patients has contributed
to a nihilistic attitude about the condition.
Author Manuscript
The main disease-related factor that hinders a correct and timely diagnosis is heterogeneity
with respect to the cardiac phenotype as well as systemic involvement. The need for a
histological demonstration of target organ amyloid infiltration has also delayed the diagnosis
as the technique is restricted to referral centers with expertise in the performance of
endomyocardial biopsy and requires skilled pathologic analysis of obtained samples.
Phenotypic variability of genetic forms of ATTR is also influenced by genetic heterogeneity,
geography, endemic vs. non-endemic aggregation, age, sex of the patient and transmitting
parent, and probably amyloid fibril composition21, 2223. Patients also rarely report a family
history because of the late presentation and incomplete penetrance.
In whom should one consider cardiac amyloid?

Author Manuscript
The diagnosis of CA requires a high index of clinical suspicion. In the past, the presence of
multi-organ involvement was over-emphasized, resulting in consideration of the diagnosis
only in the presence of extreme extra-cardiac findings such as macroglossia and periorbital
purpura that while specific, are present only in a minority of AL cases and absent in ATTR-
CA. A number of diagnostic red flags (Table 1) in a patient with otherwise unexplained left
ventricular hypertrophy or restrictive cardiomyopathy can foster the correct suspicion. A
history of carpal tunnel syndrome in ATTR (particularly if bilateral in a male), atraumatic

rupture of biceps tendon, unexplained neuropathic pain, orthostatic hypotension and a

Author Manuscript
diagnosis of “hypertrophic cardiomyopathy” after the 6th decade of life are useful clues.
Key point
Increased awareness of cardiac amyloidosis is essential to reduce under-diagnosis and
misdiagnosis, which is critical because prognosis worsens rapidly with advancing organ
dysfunction.
Pathophysiology and Natural History

Why is the heart affected in some cases of amyloidosis and not others?
The heterogeneity of systemic amyloidosis remains puzzling. Patients with the same type of
Author Manuscript
amyloidosis, whether AL or ATTR, can have different patterns of organ involvement and
different amounts of amyloid in the involved organs. Patients with systemic AL amyloidosis
without heart involvement at diagnosis are likely to develop cardiac involvement if their
culprit light-chain proteins are not eliminated and if they live long enough24. The basis for
the organ tropism of AL is not known. Studies of the immunoglobulin light-chain genetic
clones underlying AL indicate that the repertoire of light-chain germline genes used in AL is
restricted; four light-chain variable region germline genes (IGKV1-16, IGLV6-57,
IGLV2-14, IGLV3-1) account for two thirds of cases, and there is tropism for the heart with
IGLV2-14 and IGLV3-125–29 although the mechanism is unknown30. The explanation for
the differential involvement of the heart and peripheral nervous system in patients with
ATTR is also unexplained.
What is the natural history of ATTR cardiac amyloidosis?

Author Manuscript
ATTR-CA may be due to specific mutations that have a predominant involvement of the
heart (Val122Ile, Leu111Met, Ile68Leu) or ATTRwt (Table 2). Ile68Leu and Leu111Met are
mutations reported almost exclusively in Italy and Denmark, respectively, causing a severe
cardiomyopathy at an early age with a malignant course22, 31–33. In the US, ATTRwt
followed by Val122Ile and Thr60Ala mutation forms are most common34. Original
reports7, 35, 36 suggested that ATTRwt-CA had a median survival of >5 years. However,
recent reports37–39 have demonstrated that outcomes are worse with median survivals of
~3.5 years after initial evaluation40. These discrepancies are in part related to difficulty in
defining when the disease begins. Initial manifestations of TTR deposits often include
bilateral carpal tunnel syndrome41, which is found in ~70% of individuals with ATTRwt-CA
on average 5–7 years prior to the cardiac manifestations. Other manifestations include atrial
Author Manuscript
arrhythmias and a progressive decline in effort tolerance, which are difficult to definitively
attribute to amyloidosis as they occur commonly with advancing age. However, it is clear
that ATTRwt-CA can manifest as early as the fifth decade of life. Cohort studies among
subjects with ATTR-CA are predominately single center reports37, 39, 42. One, multicenter,
prospective cohort study (Transthyretin Amyloid Cohort Study – TRACS)38, demonstrated
in a small (n=29) population that mortality was high (29%) and differed between ATTRwt
(22%) and Val122Ile (79%). Larger single center studies have not confirmed this difference
in survival and multivariate analyses of TRACS and the THAOS registry data suggests that

cardiac function and not the presence of a mutation was independently associated with
mortality34, 42, 43. Progressive left ventricular dysfunction in ATTR-CA is mediated by
Author Manuscript
physiologic derangements that include reduction in chamber capacitance, declines in

chamber contractility and increases in arterial elastance.43. Patients with ATTRwt-CA have
impairments in peak VO2 and in a large series from the UK National Amyloidosis Center, a
positive troponin T, presence of a pacemaker, and NYHA class IV symptoms were
associated at baseline with a worse outcome39. Clinically, as ATTR-CA progresses, blood
pressure falls due to reduction in cardiac output and heart rate increases to compensate for a
reduced stroke volume. Every 6 months, the mean 6-minute walk distance declined by 25.8
meters, NT-pro-BNP increased by 1,816 pg/mL, and left ventricular ejection fraction fell by
3.2%38. Cardiac cachexia is particularly common with ATTR-CA, potentially mediated in
part by right heart failure, liver congestion, and possibly alterations in bowel flora.
Key point
Author Manuscript
ATTR has been considered a neurologic disease but data from worldwide registries
suggest that the heart is the main affected organ in at least half of the cases. ATTR
cardiac amyloidosis is a progressive disorder associated with significantly morbidity and
mortality.
Diagnosing Cardiac Amyloidosis

Is the ECG useful for identifying CA?
Classically, CA is characterized by low QRS voltage in spite of an increase LV wall
thickness observed with non-invasive imaging. In contemporary series, however, the
Author Manuscript
prevalence of low voltage varies with etiology, ranging from 60% in AL to 20% in
ATTR44, 45. The absence of low QRS voltages does not, therefore, preclude CA, especially
in patients with ATTRwt in whom left ventricular hypertrophy or left bundle branch block is
present in up to 30% of patients. The hallmark of CA is the disproportion between left
ventricular wall thickness and QRS voltages. While this relationship can be expressed in a
relatively complex way46, it can be assessed more simply using left ventricular wall
thickness/total QRS voltage ratio47. Pseudo-infarction patterns, present in up to 70% of
cases, can lead to an initial misdiagnosis of coronary heart disease. A significant number of
patients develop conduction disease and the presence of AV block in an older patient with
left ventricular hypertrophy should always prompt consideration of CA.
Is there a lab test to diagnose CA?

Author Manuscript
As yet, no blood test can identify TTR oligomers and diagnose ATTR-CA. In contrast, in
AL, serum and urine immunofixation and quantification of serum free light chains in
combination have a 99% sensitivity for identifying the underlying substrate for AL-CA.
Importantly, an abnormal free light chain ratio alone is not specific for AL amyloidosis as up
to 5% of the population over 65 years of age have a monoclonal gammopathy of
undetermined significance (MGUS)48. This can lead to a misdiagnosis of AL-CA in elderly
patients who actually have TTR-related CA and MGUS (up to 10% of misdiagnosis even in
referral centers)49. In addition, free light chains are filtered by the glomeruli, with renal

dysfunction resulting in increased serum concentrations. Renal dysfunction affects kappa

and lambda free chains differently and a wider reference range for FLC κ/λ ratio has been
Author Manuscript
proposed for use in patients with advanced renal failure50. The broader κ/λ ratio normal
ranges in patients with low GFR makes the diagnosis of AL-CA more challenging in
patients with renal failure. While many patients with renal failure have increased left
ventricular wall thickness and serum β2-microglobulin can be associated with increased wall
thickness51, beta-2 microglobulin amyloid deposition rarely causes meaningful cardiac
dysfunction52. Natriuretic peptides tend to be particularly high in CA, often out of
proportion from the hemodynamic burden53. Circulating light chains exert a direct toxic
effect by modulating p38 mitogen-activated protein kinase, which can directly promote NT-
pro-BNP expression.54–56 Thus, for the same range of hemodynamic abnormalities, plasma
levels of NT-pro-BNP are higher in AL compared to ATTRwt and ATTRm53. An apoptotic
effect can cause an elevation of troponins, sometimes leading to false diagnoses of acute
Author Manuscript
coronary syndrome in patients with CA hospitalized for heart failure. Accordingly, the use
of new blood tests such as the free light chain assay, NT-pro-BNP and troponin in patients
with new onset dyspnea and no obvious etiology may enable the earlier diagnosis of AL-
CA. This approach is particularly relevant to patients with pre-existing clonal plasma cell
diseases such as MGUS or smoldering myeloma or in patients with unexplained increased
wall thickness on echocardiography.
Should everyone with TTR cardiac amyloidosis have gene sequencing?

TTR gene sequencing is recommended in all cases of TTR-related amyloidosis as hereditary
types of amyloidosis cannot be distinguished from acquired types on clinical grounds alone
and a family history indicating autosomal dominant inheritance is often absent due to
incomplete and late disease penetrance. Thus sequencing the transthyretin gene in
Author Manuscript
conjunction with genetic counseling is recommended in cases in which hereditary TTR is

proven by mass spectroscopy or suspected even with a negative profile on mass
spectroscopy.
Do laboratory tests predict prognosis in CA?

There are well established prognostic models in AL amyloidosis. Current staging systems
for AL-CA are based on serum levels of N-terminal pro-brain natriuretic peptide (NT-pro-
BNP), cardiac troponin T, and the concentration of circulating free light chains. The
combination of the three biomarkers constitutes the most powerful prognostic tool available
in AL-CA and is the basis for the staging systems elaborated by the Mayo Clinic57. The
scoring system assigns one point for each of the following: NT-pro-BNP ≥ 1800 pg/mL,
Troponin T ≥0.025 ng/mL, and difference between the kappa and lambda free light chains ≥
Author Manuscript
18 mg/dL. Median survival of stage III patients was only 3.5–4.1 months. Patients with
pronounced elevations of both NT-pro-BNP and troponin have a particularly poor
prognosis58. Within stage III, NT-pro-BNP > 8500 pg/ml combined with a systolic blood
pressure less than 100 mmHg identifies patients with particularly high mortality (Stage III
B). NT-pro-BNP has also been shown to be a biomarker of clinical response and
progression, and the change in its level after therapy is a surrogate for survival59, with a
decrease associated with improved and an increase with worse overall survival60 (Figure 1).
Thus, even patients with advanced cardiac amyloid can achieve meaningful improvements in

survival if the light chains are reduced and accompanied by a cardiac response reflected by a
Author Manuscript
decline in NT-pro-BNP response, defined as a decrease in NT-pro-BNP of >30% and >300

ng/L assuming a baseline value were ≥650 ng/L. Such responses predict clinical outcome
and survival independent of therapy type, treatment class, or regimen61. Emerging data,
suggest cardiac biomarkers are also a useful prognostic marker of cardiac function in
ATTR62
Key point
In AL cardiac amyloid, light chains can directly induce secretion of high levels of
natriuretic peptides. NT-pro-BNP is a biomarker of clinical response as well as
progression of illness; with changes in its level after therapy is a surrogate for survival.
Author Manuscript
What is the role of imaging modalities in diagnosing CA?

The diagnosis of cardiac amyloidosis should be systematic and directed towards the cause as
well as the presence of amyloid protein in the myocardium. Laboratory tests, bone-tracer
scintigraphy, genetic analysis and tissue biopsy all have a place in achieving these goals. In
clinical practice, cardiac imaging is relevant to CA in three scenarios: (1) differential
diagnosis of hypertensive hypertrophic and restrictive cardiomyopathy (most common); (2)
the evaluation of patients known or suspected to have systemic AL or familial TTR
amyloidosis; and (3) in the presence of definite CA, to stage the disease and monitor the
response to therapy. Cardiac imaging must be interpreted alongside other clinical findings
and different imaging techniques should be considered complementary. The question is not
what the “best” examination is, but which is most useful and appropriate for each step of the
diagnostic and therapeutic pathway (Table 3).
Author Manuscript
What are the findings on cardiac ultrasound that raise suspicion of CA?
The echocardiographic findings of CA have been extensively reviewed elsewhere and are
summarised in Figures 2 and 363–65. Nearly all are non-specific, but in context they can be
highly suggestive of CA. The major morphological abnormalities in patients with advanced
disease are symmetrical thickening of the left ventricle, thickening of the free wall of the
right ventricle and a small pericardial effusion. Classical signs also include thickening of the
atrioventricular valves and inter-atrial septum and abnormal myocardial “texture”
characterized as a speckled appearance, although the latter is less reliable when using
harmonic imaging. Amyloidosis is the archetype for diastolic LV dysfunction, with findings
dependent on the stage of disease66. Early cardiac involvement is often associated with
impairment of relaxation which progresses to typical restrictive LV pathophysiology in
Author Manuscript
advanced symptomatic disease. Analogous changes in RV diastolic function occur in the RV

inflow, superior vena cava, and hepatic vein flow velocities67. CA is often listed as a cause
of HFpEF, but this underplays its impact on ventricular systolic performance 7, 39, 68–71.
While LVEF may be normal until the advanced stage of disease, reduction in peak systolic
wall motion velocities, especially in the longitudinal axis, are present even in early
disease72. In general, CA alters strain parameters to a much greater degree than other causes
of LV hypertrophy and is characterized by a base-to-apex strain gradient (Figure 3, upper

right panel)70, 71, 73. This is readily appreciated in parametric polar maps that show relative
Author Manuscript
apical sparing of longitudinal strain, representing an important diagnostic clue

differentiating CA from other cardiomyopathies70. In general, differentiating AL from
ATTR-CA with echocardiography is not possible but on average patients with AL-CA tend
to be more restrictive while those with ATTR-CA tend to have greater LV wall
thickness7, 39, 47.
What is the role of cardiac magnetic resonance imaging in diagnosis?

Much of the structural information derived from CMR is similar to that obtained using
echocardiography, but the ability to interrogate tissue composition with gadolinium based
contrast agents has led to an increase in the frequency of diagnosis of CA74–79. Gadolinium
is a purely extracellular agent and does not enter intact cardiomyocytes74. In some cases of
CA, there is a virtually pathognomonic appearance of global sub-endocardial late
Author Manuscript
gadolinium enhancement in a non-coronary artery territory distribution with a dark blood

pool. However, enhancement can also be diffuse and transmural or more localized and
patchy74, 76, 80. False negative studies can also arise for technical reasons when scans are
nulled using abnormal myocardium 75. This latter problem is reduced by using phase-
sensitive inversion recovery (PSIR) sequence which reduces the need for an optimal null
point setting and makes scans less operator dependent74, 81. T1 mapping is a new magnetic
resonance technique in which a quantitative signal from the myocardium is measured, before
(native T1) or after contrast administration74, 77, 78. CA substantially increases native T1 and
in AL and in ATTR-CA (Figure 3, lower right panel). T1 values are higher in AL-CA
compared with ATTR-CA, while the extracellular volume is higher in ATTR-CA than in
AL-CA79. As native T1 requires no contrast administration, it can be used in patients with
renal impairment and may be abnormal before the left ventricular wall thickens. Combined,
Author Manuscript
native T1 mapping and measures of extracellular volume (ECV) post contrast can delineate
three aspects of CA including amyloid burden or infiltration via measure of ECV, edema via
measure of native T1 and myocyte response via measure of intracellular volume. Such an
approach can provide a richer understanding of the pathophysiological processes that may be
used to monitor disease progression and response to therapy. Current limitations of the T1
imaging are the effect of confounding pathologies such as myocardial edema and platform
dependent variation in normal ranges for T1.
What is the role of myocardial scintigraphy in making a specific diagnosis?

The 99mTc-phosphate derivatives, originally developed for bone imaging, were observed to
accumulate in the early healing phase after acute myocardial infarction. 99mTc-PYP
imaging was first described as a potential diagnostic test for CA in the early 1980s following
Author Manuscript
reports describing increased cardiac uptake in patients with amyloid heart disease 82–84.
More recently in Europe, studies have evaluated the role of the tracer 99mTc-3,3-
diphosphono-1,2-propanodicarboxylic (DPD) in diagnosing CA (Figure 3, lower left
panel) 85–87. Collectively, the data show that ATTR-CA is particularly avid for bone tracers,
whereas uptake in AL-CA is either absent or only minimal. The explanation for this
differential uptake is unknown, but it has been suggested that the preferential binding to
ATTR may be a result of higher calcium content. Bone tracers seem to be useful for early
identification of ATTR-CA and may more closely correlate with amyloid load than estimates

from CMR 88 Additionally, there is also uptake in skeletal muscle, which may appear to
Author Manuscript
suppress bone activity due to masking by extensive soft-tissue uptake. In selected patients
the specificity of “bone tracer scintigraphy for ATTR CA is so high that this method can be
considered a “diagnostic standard” (see below).
Can PET be used to image and quantify amyloid?

18F-florbetapir is approved for imaging beta amyloid protein in the brain. Recent studies
have shown that it is also taken up in the heart in patients with ATTR-CA and AL-CA
(Figure 3, lower right panel). Similar findings have been reported for another beta amyloid
imaging agent 11C-PiB 89. These agents hold promise for absolute quantification of amyloid
burden.
How can one integrate the various imaging modalities into a diagnostic algorithm?
Author Manuscript
A consensus on the role of bone scintigraphy for non-invasive diagnosis of CA has emerged
(Figure 4). If CA is suspected, blood and urine should be analysed for evidence of a plasma
cell dyscrasia and imaging with bone tracer considered if ATTR-CA is a possibility. If these
tests are negative, then current evidence suggests that CA is very unlikely90. CMR scanning
may be used prior to nuclear scintigraphy as an aid to diagnosis, but a 10–20% false negative
(particularly in-CA) and false-positive rate79 (possibly more so in people of Afro-Caribbean
ancestry) for conventional contrast enhanced scans means that it does not substitute for other
tests. Until very recently, a tissue diagnosis was considered essential in all cases of suspected
CA. However, in the setting of a positive 99mTc-phosphate scan without evidence for
plasma clone on blood and urine testing, a diagnosis of ATTR-CA can be made without a
biopsy. For those patients with evidence for a plasma cell dyscrasia, a histologic diagnosis is
still required as the presence of uptake on a 99mTc-phosphate scan is not 100% specific for
Author Manuscript
ATTR-CA.
When and how should tissue biopsy be undertaken?

The diagnostic accuracy of an extra-cardiac biopsy depends on the type of amyloidosis and
on the examined tissue. In general, the yield of an extra-cardiac biopsy (abdominal fat pad,
gingiva, skin, salivary gland, or gastrointestinal tract) is higher in AL than in ATTRm; the
yield is low in ATTRwt. In AL-CA, the yield of a fat pad biopsy is >70% and is strongly
associated with whole body amyloid load. In a series of 131 patients with ATTR-CA and a
positive endomyocardial biopsy (EMB), fat aspiration was positive in 67% of ATTRm and
only 14% of ATTRwt CA.91. Thus, while a fat pad biopsy is a preferred initial site, a
negative result is insufficient to exclude the diagnosis and an endomyocardial biopsy should
be performed.
Author Manuscript
How does one confirm the precursor protein causing amyloidosis?

The ultimate goal of a biopsy, in addition to documenting amyloid infiltration, is to provide
a definite etiological classification. Immunohistochemistry remains the most widely
available method for fibril typing. Its diagnostic value is high in most cases of ATTR
amyloidosis, but the results are not always definitive in patients with AL amyloidosis. The
most frequent pitfall is the coexistence of positivity for more than one type of antisera,

typically those for TTR and lambda or kappa-chains, which are the result of the antibody
Author Manuscript
binding to circulating proteins present in the pathological specimen. In a recent series, 8/15
patients with monoclonal gammopathy, showed strong TTR staining in the histological
samples whereas mass spectrometry demonstrated light chain amyloid in 5 of these 8
patients92. Mass spectrometric analysis of amyloid is the new gold standard for fibril
typing6. This method involves laser micro-dissection and laser capture of amyloid using a
microscope followed by tryptic digestion and tandem mass spectrometry. Computer
algorithms match the peptides to a reference database, where amyloid fibril subtype can be
identified. Frequently, mass spectroscopy can identify a mutant TTR genotype, though when
a mutation is not identified, gene sequencing may be necessary.
Key point
Tissue diagnosis is required for AL amyloid and endomyocardial biopsy should be
Author Manuscript
pursued if index of suspicion is high despite a negative fat pad. Nuclear scintigraphy
agents combined with assessment for monoclonal proteins are reducing the need for
tissue confirmation in ATTR; CMR characterization of myocardial tissue can be used to
monitor disease progression and response to therapy.
Standard and Emerging Therapies for Cardiac Amyloidosis

Are there specific treatments for CA?
Diagnosis and clinical care have been held back by the erroneous belief that there are limited
effective treatments for AL-CA and by the absence of disease modifying therapy for ATTR-
CA. It is now recognized that a reduction in the precursor proteins that forms amyloid fibrils
Author Manuscript
is the key to improving prognosis in CA. Combination chemotherapy is effective in lowering

free light chains in AL-CA and orthotropic liver transplantation to remove the hepatic source
of genetically variant amyloid-forming proteins either alone or in combination with cardiac
transplant has a role in selected patients with ATTRm-CA. TTR stabilizers and silencers
hold promise for managing all forms of ATTR-CA and newer anti-fibrillar therapies aimed
at reversing cardiac dysfunction are in clinical trials. The key determinant of the efficacy of
therapy is the severity of disease at diagnosis. In advanced disease, therapy is poorly
tolerated and often ineffective93. Multidisciplinary team management and supportive care is
critical in controlling symptoms, optimizing nutritional status, maintaining cardiac function
and managing the toxicities of treatments. Collectively, therapeutic advances have begun to
shift CA from a universally fatal disease to a manageable chronic condition.
AL Cardiac Amyloidosis
Author Manuscript
What are the goals of therapy for AL cardiac amyloidosis?

The toxic amyloid-forming light chains that cause AL are produced in the bone marrow and
the clonal plasma cells in AL possess many of the same genetic abnormalities found in other
plasma cell dyscrasias 94–97. The major difference between AL and myeloma is that in AL
organ damage occurs because of the monoclonal light chains while in myeloma the organ
damage is due largely to cell mass98. Anti-plasma cell treatments for AL have evolved from

those used in myeloma, including steroids, high-dose melphalan, proteasome inhibitors and
immunomodulatory agents 99. The goals of therapy in AL-CA are to eliminate the clonal
Author Manuscript
plasma cells and provide optimal supportive care to address and control side effects of
therapy. Patients with advanced cardiac involvement cannot tolerate high-dose therapy with
autologous stem cell transplantation (SCT) and therefore patient selection for SCT has
become restrictive100, 101. Despite excellent hematologic response rates, patients with
elevations of cardiac biomarkers who are poor candidates for SCT are also at significant risk
even with standard bortezomib-based therapy with 40% dead within 2 years of diagnosis and
only 20% of responders experiencing cardiac improvement by biomarker criteria102.
However, when a response is achieved survival can be meaningfully improved.
Is halting deposition of amyloid the only treatment or can removal of amyloid and reversal
of organ dysfunction be achieved?
Author Manuscript
Hematologic response and degree of cardiac involvement are the deciding factors regarding
overall survival in systemic AL amyloidosis4. The categories of hematologic response with
initial therapy in newly diagnosed patients are complete (CR, normal FLC ratio and negative
serum and urine immunofixation), very good partial response (VGPR, difference between
involved and uninvolved free light chains < 40 mg/L or <4 mg/dl), partial response (PR,
difference between uninvolved and involved free light chains decreased > 50%), and no
response (NR)60. The frequency of cardiac responses defined as a decline in NT-pro-BNP to
<30% of baseline and of at least 300 pg/ml in 374 newly diagnosed treated AL-CA patients
were 57% with a CR, 37% with a VGPR, 18% with a PR and 4% with NR60 (Figure 1). At 6
months after starting anti-plasma cell chemotherapy, cardiac responses occurred in 26% and
progression in 45% of patients, with 85% of responders and 30% of progressors still alive
after 2 years60. Such data indicate that anti-plasma cell chemotherapy, including the use of
Author Manuscript
high-dose chemotherapy with SCT, does not enable reliable cardiac improvement for all
patients especially those with advanced cardiac involvement. Many patients with
hematologic responses continue to have persistent cardiac dysfunction despite improved
overall survival. After initial therapy, the median hematologic progression-free survival
(PFS) is 1 to 4 years, depending on the type of initial therapy. The PFS for the 25% of newly
diagnosed patients who were candidates for SCT appears to be higher than that of patients
receiving standard therapy with bortezomib-based combinations. Indeed, about 80% of the
long-term post-SCT survivors with CR have organ responses.101. At hematologic relapse,
the majority of patients have stage 2 or 3 chronic renal disease and stage 2 cardiac disease
(see Figure 1)24.
The unmet need for patients is therapy that reverses organ damage and dysfunction30.
Several approaches are in clinical trials at this time, including three monoclonal antibody
Author Manuscript
based therapies that may enhance phagocytic clearance of amyloid deposits. The anti-
amyloid 11–1F4 monoclonal was used in a phase I trial (NCT02245867) in AL patients with
relapsed refractory disease, and cardiac and GI organ responses were reported in 3 of the
first 6 patients treated103. Employing a different approach in their phase I trial
(NCT01777243), based on the fact that amyloid fibril deposits always contain the non-
fibrillar normal plasma protein, serum amyloid P component (SAP), investigators from the
National Amyloidosis Center in the UK used a combination of two agents. The drug, R-1-

[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC),

Author Manuscript
efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can
be specifically targeted by therapeutic IgG anti-SAP antibodies, inciting an inflammatory
multinucleated giant cell response104. In this phase I trial, whole-body scans using iodinated
SAP demonstrated depletion of hepatic amyloid in 50% of patients with liver involvement.
There were also reductions in in C3 and spikes in CRP, indicating ongoing inflammation.
Patients with cardiac involvement were excluded from the trial105. The third, and furthest
along in clinical development, is the anti-amyloid monoclonal NEOD001 that binds to an
epitope in amyloid fibrils. In a phase 1/2 trial (NCT01707264), previously treated AL
patients who were in hematologic remission with biomarker evidence of on-going organ
damage, received NEOD001 monthly106. There were no toxicities and organ responses were
seen in majorities of both cardiac (57%) and renal (60%) patients. NEOD001 is now in a
phase 3 trial for newly diagnosed patients with cardiac involvement (NCT02312206), in
Author Manuscript
which patients receive bortezomib-based therapy and are randomized to receive either
NEOD001 or saline monthly.
What are the mechanisms of therapeutic efficacy (reduction in precursor protein/amyloid

production versus amyloid clearance)?
Therapeutic efficacy in AL has two dimensions, survival and improvement in organ
function. Hematologic response to therapy is measured in terms of the reduction or
elimination of the clonal plasma cells that produce the culprit light-chain protein. Patients
who achieve a hematologic CR or VGPR live longer than those who do not60. Improvement
in organ function is measured with cardiac and renal biomarkers and, for patients with other
organs involved, with a mix of exam and laboratory findings such as normalization of
orthostatic symptoms and vital signs for patients with autonomic neuropathy or of liver span
and alkaline phosphatase for those with hepatic involvement107. Patients who achieve
Author Manuscript
cardiac biomarker responses live longer than those who do not 59, 60, 108.
Hematologic responses based on changes in the serum free light chain assay are validated
surrogates for the impact of therapy on the clonal marrow cells. With elimination or near
elimination of the culprit light-chain protein, patients usually experience improvement in
organ function and in their QOL. However, while hematologic response is necessary for
organ response, it is not sufficient30. There is general consensus that both early cardiac death
and survival with persistent organ damage are critical unmet clinical challenges.
What factors influence treatment decisions (rapidity of response, toxicity and physiologic
reserve)?
The initial evaluation of newly diagnosed patients with AL is focused on the extent of both
Author Manuscript
cardiac and extra-cardiac organ involvement, physiologic reserve and the character of the
clonal marrow plasma cells109. In a cohort of over 800 patients from 6 countries, 26% were
NYHA class 2 or 3, 25% CKD Stage 3, and 15% CKD Stage 4 or 5; 50% were Mayo
cardiac stage II with either Troponin T or NTpro-BNP above the threshold and 34% were
cardiac stage III with both elevated; 19% had liver and 16% peripheral nervous system
involvement60.

Who is eligible for SCT?

Author Manuscript
Eligibility criteria for high-dose therapy with SCT include age less than 65, Karnofsky
performance status of 80% or higher, adequate cardiac function (systolic blood pressure > 90
mm Hg, ejection fraction >45%, troponin T <0.06 ng/ml, NT-proBNP < 8,500 pg/ml or
pulmonary artery saturation of >55%) and compensated or controlled orthostatic changes in
blood pressure110. Patients who are Mayo cardiac stage III or CKD 4 are rarely eligible;
young patients on hemodialysis, however, who are cardiac stage I or II are often eligible for
SCT. Most patients are not eligible for SCT and receive bortezomib-based therapy with
doses adjusted for frailty, impaired liver function and NYHA class111, 112. Bortezomib may
not be the first choice of proteasome inhibitors for patients with peripheral neuropathy
because of the risk of worsened neuropathy due to the drug; alternatives exist113. After SCT,
consolidation is recommended for AL patients who do not achieve a CR (in myeloma post-
SCT consolidation is recommended for all)4, 114. For patients treated with bortezomib-based
Author Manuscript
therapy, the lack of a hematologic response after 2 cycles is usually a signal to change
therapy and, in most cases, bortezomib and dexamethasone will be retained but other agents
such as melphalan or immune-modulatory drugs are added109.
What is the data on efficacy of therapies?

The mix of therapies used to treat newly diagnosed patients with AL and the reported
outcomes are recounted in Supplementary Table 1. High-dose therapy with SCT and
bortezomib-based combination chemotherapy are the two options used most frequently in
the USA100. In the UK and EU, however, SCT is less often employed and other regimens
such as oral melphalan and dexamethasone or oral cyclophosphamide, thalidomide and
dexamethasone are commonly used99, 115, 116. Doses of agents in all of these regimens are
often adjusted for age, frailty, renal and hepatic function, and NYHA class.
Author Manuscript
Key point
New targeted plasma cell therapies have rapidly expanded the treatment option for
patients with AL cardiac amyloid, improving outcomes for patients with earlier stage
disease.
ATTR Cardiac Amyloidosis

What are the targets for therapy in TTR?
Current treatment for ATTR-CA is focused on various stages in the TTR amyloid cascade
including silencing of TTR production, TTR stabilization and amyloid clearance from
Author Manuscript
tissues (Figure 5)117–119. Because 95% of TTR protein is produced by the liver, orthotopic
liver transplantation (OLT) has been employed in ATTRm to replace amyloid forming
mutant with wild type TTR and theoretically arrest amyloid formation. The majority of
OLTs for ATTRm amyloid are performed in patients with a primary neuropathic phenotype,
most commonly the Val30Met variant120. OLT is considered a preventative measure to
forestall the development of the sensorimotor neuropathy or multiple organ involvement.
Survival after liver transplantation in Val30Met patients is > 50% at 20 years120. Since the

liver function of TTR liver transplant recipients is otherwise normal, their livers have been
Author Manuscript
transplanted into high risk recipients (“domino liver transplant”), causing TTR amyloidosis
in recipients several years later121. While survival is prolonged by liver transplantation120,
there is slowing but not arrest of cardiac dysfunction. This is attributed to deposition of wild
type TTR amyloid in the heart from the transplanted liver causing progressive cardiac
dysfunction. Patients with fragmented ATTR fibrils (type A) developed HF after OLT while
those who had intact ATTR fibrils (type B) did not deteriorate to the same degree122. The
scarcity of organ availability, the need for lifelong immunosuppression and the relatively
older age of affected subjects make transplantation a suboptimal option for treating ATTR-
CA.
Both RNA interference (RNAi) and antisense oligonucleotides (ASOs) have been used to
inhibit hepatic expression of amyloid forming TTR. These therapies capitalize on
endogenous cellular mechanism for controlling gene expression in which siRNAs or ASOs,
Author Manuscript
mediates the destruction of target messenger RNA (mRNA) essential for TTR protein
production. These agents cause a robust and durable reduction in genetic expression
(knockdown) of TTR and retinol binding protein123–125. Both methods of silencing have
completed recruitment for phase III trials in ATTR peripheral neuropathy with results
expected in 2017 but a phase III trial in ATTR cardiomyopathy was recently suspended with
unexpected adverse impact on those receiving active treatment (Supplementary Table 2).
TTR stabilizers have demonstrated efficacy in FAP126, 127 but their role in ATTR-CA is
unknown. Diflunisal, a nonsteroidal anti-inflammatory drug, binds and stabilizes common
familial TTR variants against acid-mediated fibril formation in vitro and has been tested in
human clinical trials126. Use of diflunisal is controversial given the known consequences of
chronic inhibition of cyclooxygenase enzymes including gastrointestinal bleeding, renal
Author Manuscript
dysfunction, fluid retention, and hypertension that may precipitate HF in vulnerable

individuals. Tafamidis is a novel compound that binds to the thyroxine-binding sites of the
TTR tetramer, inhibiting its dissociation into monomers128 and blocking the rate-limiting
step in the TTR amyloid forming cascade (Figure 5).
Doxycycline disrupts fibril formation129 and when combined with the bile salt,
tauroursodeoxycholic acid, demonstrated a synergistic effect on removal of tissue TTR
deposits in an animal model, leading to open label trials in humans130. Epigallocatechin
gallate (EGCG), the most abundant flavonoid in green tea, inhibits amyloid fibril formation
in vitro, leading to open label trials in ATTR-CA131, 132.
What are the results of recent trials in TTR?

Author Manuscript
A majority of the trials completed to date have been small (<100 subjects), phase II, open
label, intermediate duration (1–2 years) with primary endpoints being the NIS-LL and QOL
for ATTR peripheral neuropathy and echocardiographic, biomarkers and six minute hall
walk for ATTR-CA (Supplementary Table 2). Trials for neuropathy are further along than
those for cardiomyopathy. Trials to date have demonstrated short term efficacy limited to
either a surrogate maker (TTR stabilization) and/or the absence or slowing of disease
progression, albeit with no control group.

The only phase III trials completed to date involved administration of diflunisal126 and
tafamidis127, 133, both in FAP. In the diflunisal trial, echocardiography demonstrated a
Author Manuscript
prevalence of presumptive CA in >50% of these FAP patients but analysis of

echocardiographic variables including strain did not show significant differences with
treatment, though statistical power was low134. Tafamidis, in patients with early-stage
ATTRm due to Val30Met127, slowed progression of neurological symptoms and early
treatment was associated with greater preservation of neurologic function133, which was not
confirmed in late phase FAP135. Thus, early administration of tafamidis seems to be
important for its efficacy. Additionally, all previous trials employed a dose of 20 mg but an
80 mg dose is being tested in an ongoing phase III trial, with biochemical data suggesting
that a higher dose may be required for TTR stabilization136. Five year safety data in a small
cohort has been reassuring in that tafamidis was generally well tolerated at 20 mg, though
efficacy data showed few patients with ATTR-CA were clinically stabilized at 3.5 years.
Author Manuscript
What therapies are in late phase development?

Currently there is 1 clinical trial for ATTR-CA in Phase III involving tafamidis. A second
trial with revusiran, a siRNA, was recently stopped and the development of the drug
suspended. Both of these trials were placebo controlled with allocation to active therapy of
~2:1 and a fixed study duration that encourages participation by subjects who have a
progressive, life threatening condition. Differences in study populations include a focus on
ATTRm in the case of revusiran while the other (ATTR-ACT) enrolled both ATTRm and
ATTRwt. The ATTR-ACT trial of tafamidis is expected to conclude in 2018.
Key point
The biologic process underlying ATTR-CA has led to the development of numerous
Author Manuscript
therapies that are currently in late phase clinical trials. A recent trial of a siRNA for
transthyretin in CA was stopped prematurely due to an unexpected worsening of
subject’s clinical status.
Cardiac Replacement therapy – Transplant and VAD

Is AL amyloidosis a contraindication to cardiac transplantation?
AL-CA was previously considered a contraindication to orthotopic heart transplant (OHT)
because of concerns regarding worse long term outcomes due to the amyloid involvement of
other organs or the risk of recurrent amyloid in the graft137. However, the development of
multiple therapies targeted at the monoclonal protein including high dose chemotherapy
Author Manuscript
with SCT has made long term control of the plasma cell dyscrasia possible. Accordingly,
series in selected patients for whom heart transplant was performed at experienced centers
with established multi-disciplinary collaborations followed by either stem cell transplant or
ongoing chemotherapy have reported outcomes comparable to other subjects with restrictive
cardiomyopathies.138–141 Additionally, an analysis of UNOS data shows improved post-
OHT survival in patients with CA, in part due to improved patient selection including an
increase in those with ATTR-CA.141. The one year survival post OHT in UNOS for CA

(including both AL-CA and ATTR-CA) from 2010 to 2012 was 81.6%. Accordingly, current
guidelines endorse consideration of selected patients with either AL and ATTR-CA142.
Author Manuscript
What additional testing is required for heart transplant evaluation?

The degree of organs involved is an important prognostic variable influencing the outcomes
of patients with AL undergoing SCT. Accordingly, multiple other organ systems must be
thoroughly assessed for the functional effect of amyloid and if necessary for the anatomic/
histologic degree of amyloid infiltration. Specific guidelines by the ISHLT have been
published (see Table 4).142
Do outcomes differ in subjects with AL vs. TTR cardiac amyloidosis undergoing OHT?
Data from Columbia University Medical Center, has shown better survival for ATTR-CA
subjects (n=10) than AL-CA (n=16) undergoing OHT with transplants performed from
Author Manuscript
1999–2008. However, a more contemporary series from Stanford has shown better survival
in AL (n=10) than TTR (n=9) CA140. Multicenter data obtained as part of the International
Consortium in Cardiac Amyloid Transplantation (iCCAT) has demonstrated that outcomes
of patients with CA do not differ statistically from those with AL compared to TTR143.
How should the plasma clone be managed in patients with AL cardiac amyloid undergoing
OHT?
Control of the underlying plasma cell dyscrasia is critical to successful outcomes in AL
cardiac amyloid. Data from iCCAT demonstrates that survival without recurrent amyloid
post OHT is higher in those who receive chemotherapy prior to OHT than those who did not
receive chemotherapy144. Accordingly, upfront plasma cell therapy to achieve a complete or
very good hematologic response while waiting for OHT is increasingly being advised. While
Author Manuscript
high or dose adjusted melphalan with SCT remains the most cytotoxic therapy for AL
amyloid, combination therapy using proteasome inhibitors has been shown to be effective in
AL-CA patients post OHT140.
How can I bridge my patient with advanced cardiac amyloid to an OHT?

The options for mechanical circulatory support as a bridge to OHT for CA patients is
confounded by the small ventricular chamber size and increased wall thickness that increase
the risk for suction events, right heart failure and overall worse outcomes in very small series
reported to date.145 Survival with a VAD is strongly associated with left ventricular end
diastolic diameter146. Other forms of circulatory support including intra-aortic balloon
pump, BiVAD or total artificial heart (the latter employed given the need for biventricular
support) have been employed though survival at one year is reduced if circulatory support is
Author Manuscript
required147. A theoretical analysis using a cardiovascular simulation of a novel micro-VAD

for CA has shown that sourcing of blood from the left atrium was not associated with
suction, as assessed by declines in left ventricular end systolic volumes, but did lower left
atrial pressure and increase cardiac output and blood pressure in subjects148. Whether such
an approach can be effective in-vivo in CA requires additional study.

Key point
Author Manuscript
While the overall goal is to eliminate the need for OHT in CA, advances in patient
selection and available therapies have made intermediate term outcomes of OHT in CA
comparable to non-amyloid patients.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Sources of Funding: Dr. Maurer is supported by a Mid-career Mentoring Award from the NIA (AG036778-06).
Author Manuscript
References
1. Glenner GG, Ein D, Eanes ED, Bladen HA, Terry W, Page DL. Creation of “amyloid” fibrils from
Bence Jones proteins in vitro. Science. 1971; 174:712–4. [PubMed: 5123421]
2. Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003; 349:583–96.
[PubMed: 12904524]
3. Kyle RA. Amyloidosis: a convoluted story. Br J Haematol. 2001; 114:529–38. [PubMed: 11552976]
4. Merlini G, Comenzo RL, Seldin DC, Wechalekar A, Gertz MA. Immunoglobulin light chain
amyloidosis. Expert Rev Hematol. 2014; 7:143–56. [PubMed: 24350907]
5. Cohen AS, Calkins E. Electron microscopic observations on a fibrous component in amyloid of
diverse origins. Nature. 1959; 183:1202–3. [PubMed: 13657054]
6. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan A. Classification of
amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical
biopsy specimens. Blood. 2009; 114:4957–9. [PubMed: 19797517]
Author Manuscript
7. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, Salvi F, Ciliberti P, Pastorelli F,
Biagini E, Coccolo F, Cooke RM, Bacchi-Reggiani L, Sangiorgi D, Ferlini A, Cavo M, Zamagni E,
Fonte ML, Palladini G, Salinaro F, Musca F, Obici L, Branzi A, Perlini S. Systemic cardiac
amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009; 120:1203–
12. [PubMed: 19752327]
8. Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, Kurland LT. Incidence and
natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989.
Blood. 1992; 79:1817–22. [PubMed: 1558973]
9. Pinney JH, Smith CJ, Taube JB, Lachmann HJ, Venner CP, Gibbs SD, Dungu J, Banypersad SM,
Wechalekar AD, Whelan CJ, Hawkins PN, Gillmore JD. Systemic amyloidosis in England: an
epidemiological study. Br J Haematol. 2013; 161:525–32. [PubMed: 23480608]
10. Hemminki K, Li X, Forsti A, Sundquist J, Sundquist K. Incidence and survival in non-hereditary
amyloidosis in Sweden. BMC Public Health. 2012; 12:974. [PubMed: 23148499]
11. Muchtar E, Buadi FK, Dispenzieri A, Gertz MA. Immunoglobulin Light-Chain Amyloidosis: From
Basics to New Developments in Diagnosis, Prognosis and Therapy. Acta Haematol. 2016;
Author Manuscript
135:172–90. [PubMed: 26771835]

12. Galat A, Guellich A, Bodez D, Slama M, Dijos M, Zeitoun DM, Milleron O, Attias D, Dubois-
Rande JL, Mohty D, Audureau E, Teiger E, Rosso J, Monin JL, Damy T. Aortic stenosis and
transthyretin cardiac amyloidosis: the chicken or the egg? Eur Heart J. 2016; 37:3525–3531.
[PubMed: 26908951]
13. Maurer MS. Noninvasive Identification of ATTRwt Cardiac Amyloid: The Re-emergence of
Nuclear Cardiology. Am J Med. 2015; 128:1275–80. [PubMed: 26091765]
14. Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-
Enari S, Paetau A, Tienari PJ, Myllykangas L. Senile systemic amyloidosis affects 25% of the very

aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based
autopsy study. Ann Med. 2008; 40:232–9. [PubMed: 18382889]
Author Manuscript
15. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan DR, Dunlay SM, Roger VL, Gertz
MA, Dispenzieri A, Zeldenrust SR, Redfield MM. Left ventricular amyloid deposition in patients
with heart failure and preserved ejection fraction. JACC Heart Fail. 2014; 2:113–22. [PubMed:
24720917]
16. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016; 387:2641–54.
[PubMed: 26719234]
17. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos
M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type
transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J.
2015; 36:2585–94. [PubMed: 26224076]
18. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic
transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015; 22:171–4.
[PubMed: 26123279]
19. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, Mosley TH, Butler KR,
Author Manuscript
Boerwinkle E, Solomon SD. The amyloidogenic V122I transthyretin variant in elderly black
Americans. N Engl J Med. 2015; 372:21–9. [PubMed: 25551524]
20. Lousada I, Comenzo RL, Landau H, Guthrie S, Merlini G. Light Chain Amyloidosis: Patient
Experience Survey from the Amyloidosis Research Consortium. Adv Ther. 2015; 32:920–8.
[PubMed: 26498944]
21. Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ,
Gottlieb SS, Shah SJ, Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, Hummel
SL, Kristen AV, Damy T, Plante-Bordeneuve V, Coelho T, Mundayat R, Suhr OB, Waddington
Cruz M, Rapezzi C. Investigators T. Genotype and Phenotype of Transthyretin Cardiac
Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;
68:161–72. [PubMed: 27386769]
22. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey:
initial report on clinical manifestations in patients with hereditary and wild-type transthyretin
amyloidosis. Curr Med Res Opin. 2013; 29:63–76. [PubMed: 23193944]
23. Arvidsson S, Pilebro B, Westermark P, Lindqvist P, Suhr OB. Amyloid Cardiomyopathy in
Author Manuscript
Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition.
PLoS One. 2015; 10:e0143456. [PubMed: 26600306]
24. Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Blade J, Fermand JP, Hassoun
H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A,
Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed
systemic AL amyloidosis. Blood. 2014; 124:2498–506. [PubMed: 25202139]
25. Comenzo RL, Wally J, Kica G, Murray J, Ericsson T, Skinner M, Zhang Y. Clonal immunoglobulin
light chain variable region germline gene use in AL amyloidosis: association with dominant
amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol.
1999; 106:744–51. [PubMed: 10468868]
26. Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera GA. The tropism of organ involvement in
primary systemic amyloidosis: contributions of Ig V(L) germ line gene use and clonal plasma cell
burden. Blood. 2001; 98:714–20. [PubMed: 11468171]
27. Abraham RS, Geyer SM, Price-Troska TL, Allmer C, Kyle RA, Gertz MA, Fonseca R.
Author Manuscript
Immunoglobulin light chain variable (V) region genes influence clinical presentation and outcome
in light chain-associated amyloidosis (AL). Blood. 2003; 101:3801–8. [PubMed: 12515719]
28. Bodi K, Prokaeva T, Spencer B, Eberhard M, Connors LH, Seldin DC. AL-Base: a visual platform
analysis tool for the study of amyloidogenic immunoglobulin light chain sequences. Amyloid.
2009; 16:1–8. [PubMed: 19291508]
29. Perfetti V, Palladini G, Casarini S, Navazza V, Rognoni P, Obici L, Invernizzi R, Perlini S, Klersy
C, Merlini G. The repertoire of lambda light chains causing predominant amyloid heart
involvement and identification of a preferentially involved germline gene, IGLV1–44. Blood.
2012; 119:144–50. [PubMed: 22067386]

30. Weiss BM, Wong SW, Comenzo RL. Beyond the plasma cell: emerging therapies for
immunoglobulin light chain amyloidosis. Blood. 2016; 127:2275–80. [PubMed: 26907632]
Author Manuscript
31. Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, Biagini E, Lorenzini M, Grigioni F,
Leone O, Cappelli F, Palladini G, Rimessi P, Ferlini A, Arpesella G, Pinna AD, Merlini G, Perlini
S. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with
exclusively cardiac phenotype: an Italian perspective. Eur Heart J. 2013; 34:520–8. [PubMed:
22745357]
32. Svendsen IH, Steensgaard-Hansen F, Nordvag BY. A clinical, echocardiographic and genetic
characterization of a Danish kindred with familial amyloid transthyretin methionine 111 linked
cardiomyopathy. Eur Heart J. 1998; 19:782–9. [PubMed: 9717013]
33. Sattianayagam PT, Hahn AF, Whelan CJ, Gibbs SD, Pinney JH, Stangou AJ, Rowczenio D,
Pflugfelder PW, Fox Z, Lachmann HJ, Wechalekar AD, Hawkins PN, Gillmore JD. Cardiac
phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin
alanine 60 variant. Eur Heart J. 2012; 33:1120–7. [PubMed: 21992998]
34. Maurer MSHM, Grogan M, Dispenzieri A, Witteles R, Drachman B, Judge DP, Lenihan DJ,
Gottlieb SS, Shah SJ, Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, Hummel
Author Manuscript
SL, Kristen AV, Damy T, Planté-Bordeneuve V, Coelho R, Mundayat R, Suhr OB, Waddington
Cruz M, Rapezzi C. on behalf of THAOS Investigators. Genotype and Phenotype of Transthyretin-
Related Cardiac Amyloidosis in the United States: A Report from the Transthyretin Amyloid
Outcome Survey (THAOS). JACC. 2016; 68:161–72. [PubMed: 27386769]
35. Kyle RA, Spittell PC, Gertz MA, Li CY, Edwards WD, Olson LJ, Thibodeau SN. The premortem
recognition of systemic senile amyloidosis with cardiac involvement. Am J Med. 1996; 101:395–
400. [PubMed: 8873510]
36. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with
heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005;
165:1425–9. [PubMed: 15983293]
37. Connors LH, Sam F, Skinner M, Salinaro F, Sun F, Ruberg FL, Berk JL, Seldin DC. Heart Failure
Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin:
A Prospective, Observational Cohort Study. Circulation. 2016; 133:282–90. [PubMed: 26660282]
38. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, Falk RH, Cheung KN, Patel
AR, Pano A, Packman J, Grogan DR. Prospective evaluation of the morbidity and mortality of
Author Manuscript
wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis
Cardiac Study (TRACS). Am Heart J. 2012; 164:222–228. e1. [PubMed: 22877808]
39. Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P, Wechalekar A, Gibbs
SD, Venner CP, Wassef N, McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore
JD, Lachmann HJ. Senile systemic amyloidosis: clinical features at presentation and outcome. J
Am Heart Assoc. 2013; 2:e000098. [PubMed: 23608605]
40. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL,
Maleszewski JJ, Dispenzieri A. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis
and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016; 68:1014–20.
[PubMed: 27585505]
41. Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T, Doden T, Koyama J, Yanagisawa S,
Ikeda S. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR
(ATTRwt) amyloidosis. Amyloid. 2016; 23:58–63. [PubMed: 26852880]
42. Givens RC, Russo C, Green P, Maurer MS. Comparison of cardiac amyloidosis due to wild-type
and V122I transthyretin in older adults referred to an academic medical center. Aging health.
Author Manuscript
2013; 9:229–235. [PubMed: 24073013]

43. Bhuiyan T, Helmke S, Patel AR, Ruberg FL, Packman J, Cheung K, Grogan D, Maurer MS.
Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis
secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study
(TRACS). Circ Heart Fail. 2011; 4:121–8. [PubMed: 21191093]
44. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low
QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014; 114:1089–
93. [PubMed: 25212550]

45. Mussinelli R, Salinaro F, Alogna A, Boldrini M, Raimondi A, Musca F, Palladini G, Merlini G,

Perlini S. Diagnostic and prognostic value of low QRS voltages in cardiac AL amyloidosis. Ann
Author Manuscript
Noninvasive Electrocardiol. 2013; 18:271–80. [PubMed: 23714086]

46. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive
voltage/mass relation. Am J Cardiol. 1982; 49:9–13. [PubMed: 6459025]
47. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, Gagliardi C, Milandri A,
Rapezzi C, Falk RH. Left ventricular structure and function in transthyretin-related versus light-
chain cardiac amyloidosis. Circulation. 2014; 129:1840–9. [PubMed: 24563469]
48. Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton LJ 3rd, Colby CL, Therneau TM,
Clark R, Kumar SK, Bradwell A, Fonseca R, Jelinek DF, Rajkumar SV. Prevalence and risk of
progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective
population-based cohort study. Lancet. 2010; 375:1721–8. [PubMed: 20472173]
49. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins
PN. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med. 2002;
346:1786–91. [PubMed: 12050338]
50. Hutchison CA, Harding S, Hewins P, Mead GP, Townsend J, Bradwell AR, Cockwell P.
Author Manuscript
Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic
kidney disease. Clin J Am Soc Nephrol. 2008; 3:1684–90. [PubMed: 18945993]
51. Masuda M, Ishimura E, Ochi A, Tsujimoto Y, Tahahra H, Okuno S, Tabata T, Nishizawa Y, Inaba
M. Serum beta2-microglobulin correlates positively with left ventricular hypertrophy in long-term
hemodialysis patients. Nephron Clin Pract. 2014; 128:101–6. [PubMed: 25376242]
52. Noel LH, Zingraff J, Bardin T, Atienza C, Kuntz D, Drueke T. Tissue distribution of dialysis
amyloidosis. Clin Nephrol. 1987; 27:175–8. [PubMed: 3555909]
53. Perfetto F, Bergesio F, Grifoni E, Fabbri A, Ciuti G, Frusconi S, Angelotti P, Spini V, Cappelli F.
Different NT-proBNP circulating levels for different types of cardiac amyloidosis. J Cardiovasc
Med (Hagerstown). 2016; 17:810–7. [PubMed: 26765991]
54. Shi J, Guan J, Jiang B, Brenner DA, Del Monte F, Ward JE, Connors LH, Sawyer DB, Semigran
MJ, Macgillivray TE, Seldin DC, Falk R, Liao R. Amyloidogenic light chains induce
cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK
pathway. Proc Natl Acad Sci U S A. 2010; 107:4188–93. [PubMed: 20150510]
55. Brenner DA, Jain M, Pimentel DR, Wang B, Connors LH, Skinner M, Apstein CS, Liao R. Human
Author Manuscript
amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular
oxidant stress. Circ Res. 2004; 94:1008–10. [PubMed: 15044325]
56. Liao R, Jain M, Teller P, Connors LH, Ngoy S, Skinner M, Falk RH, Apstein CS. Infusion of light
chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse
hearts. Circulation. 2001; 104:1594–7. [PubMed: 11581134]
57. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, Laumann K, Zeldenrust SR,
Leung N, Dingli D, Greipp PR, Lust JA, Russell SJ, Kyle RA, Rajkumar SV, Gertz MA. Revised
prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum
free light chain measurements. J Clin Oncol. 2012; 30:989–95. [PubMed: 22331953]
58. Dietrich S, Schonland SO, Benner A, Bochtler T, Kristen AV, Beimler J, Hund E, Zorn M,
Goldschmidt H, Ho AD, Hegenbart U. Treatment with intravenous melphalan and dexamethasone
is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain
amyloidosis and severe cardiac involvement. Blood. 2010; 116:522–8. [PubMed: 20375312]
59. Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, Falk R, Wells K,
Author Manuscript
Solomon A, Wechalekar A, Zonder J, Dispenzieri A, Gertz M, Streicher H, Skinner M, Kyle RA,

Merlini G. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-
chain amyloidosis. Leukemia. 2012; 26:2317–25. [PubMed: 22475872]
60. Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Schonland S,
Hegenbart U, Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G. New
criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light
chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol. 2012;
30:4541–9. [PubMed: 23091105]

61. Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, Maurer MS, Sanchorawala V,
Wechalekar A, Palladini G, Comenzo RL. Rationale, application and clinical qualification for NT-
Author Manuscript
proBNP as a surrogate end point in pivotal clinical trials in patients with AL amyloidosis.
Leukemia. 2016; 30:1979–1986. [PubMed: 27416985]
62. Grogan MSC, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski
JJ, Dispenzieri A. Natural History of Wild Type Transthyretin Cardiac Amyloidosis and Risk
Stratification Using a Novel Staging System. J Am Coll Cardiol. 2016; 68:1014–20. [PubMed:
27585505]
63. Damy T, Maurer MS, Rapezzi C, Plante-Bordeneuve V, Karayal ON, Mundayat R, Suhr OB,
Kristen AV. Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related
cardiomyopathy. Open Heart. 2016; 3:e000289. [PubMed: 26870387]
64. Rapezzi C, Lorenzini M, Longhi S, Milandri A, Gagliardi C, Bartolomei I, Salvi F, Maurer MS.
Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015; 20:117–24. [PubMed: 25758359]
65. Koyama J, Ikeda S, Ikeda U. Echocardiographic assessment of the cardiac amyloidoses. Circ J.
2015; 79:721–34. [PubMed: 25766406]
66. Klein AL, Hatle LK, Burstow DJ, Seward JB, Kyle RA, Bailey KR, Luscher TF, Gertz MA, Tajik
Author Manuscript
AJ. Doppler characterization of left ventricular diastolic function in cardiac amyloidosis. J Am

Coll Cardiol. 1989; 13:1017–26. [PubMed: 2647814]
67. Klein AL, Hatle LK, Burstow DJ, Taliercio CP, Seward JB, Kyle RA, Bailey KR, Gertz MA, Tajik
AJ. Comprehensive Doppler assessment of right ventricular diastolic function in cardiac
amyloidosis. J Am Coll Cardiol. 1990; 15:99–108. [PubMed: 2295749]
68. Liu D, Niemann M, Hu K, Herrmann S, Stork S, Knop S, Ertl G, Weidemann F. Echocardiographic
evaluation of systolic and diastolic function in patients with cardiac amyloidosis. Am J Cardiol.
2011; 108:591–8. [PubMed: 21807135]
69. Di Bella G, Minutoli F, Pingitore A, Zito C, Mazzeo A, Aquaro GD, Di Leo R, Recupero A,
Stancanelli C, Baldari S, Vita G, Carerj S. Endocardial and epicardial deformations in cardiac
amyloidosis and hypertrophic cardiomyopathy. Circ J. 2011; 75:1200–8. [PubMed: 21427499]
70. Phelan D, Thavendiranathan P, Popovic Z, Collier P, Griffin B, Thomas JD, Marwick TH.
Application of a parametric display of two-dimensional speckle-tracking longitudinal strain to
improve the etiologic diagnosis of mild to moderate left ventricular hypertrophy. J Am Soc
Echocardiogr. 2014; 27:888–95. [PubMed: 24874973]
Author Manuscript
71. Ternacle J, Bodez D, Guellich A, Audureau E, Rappeneau S, Lim P, Radu C, Guendouz S, Couetil
JP, Benhaiem N, Hittinger L, Dubois-Rande JL, Plante-Bordeneuve V, Mohty D, Deux JF, Damy
T. Causes and Consequences of Longitudinal LV Dysfunction Assessed by 2D Strain
Echocardiography in Cardiac Amyloidosis. JACC Cardiovasc Imaging. 2016; 9:126–38. [PubMed:
26777222]
72. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity,
strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac
amyloidosis. Circulation. 2003; 107:2446–52. [PubMed: 12743000]
73. Senapati A, Sperry BW, Grodin JL, Kusunose K, Thavendiranathan P, Jaber W, Collier P, Hanna
M, Popovic ZB, Phelan D. Prognostic implication of relative regional strain ratio in cardiac
amyloidosis. Heart. 2016; 102:748–54. [PubMed: 26830665]
74. Fontana M, Chung R, Hawkins PN, Moon JC. Cardiovascular magnetic resonance for amyloidosis.
Heart Fail Rev. 2015; 20:133–44. [PubMed: 25549885]
75. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, Sheppard MN, Poole-Wilson
Author Manuscript
PA, Hawkins PN, Pennell DJ. Cardiovascular magnetic resonance in cardiac amyloidosis.
Circulation. 2005; 111:186–93. [PubMed: 15630027]
76. Ruberg FL, Appelbaum E, Davidoff R, Ozonoff A, Kissinger KV, Harrigan C, Skinner M,
Manning WJ. Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in
light-chain cardiac amyloidosis. Am J Cardiol. 2009; 103:544–9. [PubMed: 19195518]
77. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB, Ferreira VM, Whelan CJ,
Myerson SG, Robson MD, Hawkins PN, Neubauer S, Moon JC. Noncontrast T1 mapping for the
diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging. 2013; 6:488–97. [PubMed:
23498672]

78. Fontana M, Banypersad SM, Treibel TA, Maestrini V, Sado DM, White SK, Pica S, Castelletti S,
Piechnik SK, Robson MD, Gilbertson JA, Rowczenio D, Hutt DF, Lachmann HJ, Wechalekar AD,
Author Manuscript
Whelan CJ, Gillmore JD, Hawkins PN, Moon JC. Native T1 mapping in transthyretin amyloidosis.
JACC Cardiovasc Imaging. 2014; 7:157–65. [PubMed: 24412190]
79. Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Gilbertson JA, Lachmann HJ,
Wechalekar A, Gillmore JD, Whelan CJ, Hawkins PN, Anderson LJ. CMR-based differentiation of
AL and ATTR cardiac amyloidosis. JACC Cardiovasc Imaging. 2014; 7:133–42. [PubMed:
24412186]
80. Syed IS, Glockner JF, Feng D, Araoz PA, Martinez MW, Edwards WD, Gertz MA, Dispenzieri A,
Oh JK, Bellavia D, Tajik AJ, Grogan M. Role of cardiac magnetic resonance imaging in the
detection of cardiac amyloidosis. JACC Cardiovasc Imaging. 2010; 3:155–64. [PubMed:
20159642]
81. Kellman P, Arai AE, McVeigh ER, Aletras AH. Phase-sensitive inversion recovery for detecting
myocardial infarction using gadolinium-delayed hyperenhancement. Magn Reson Med. 2002;
47:372–83. [PubMed: 11810682]
82. Wizenberg TA, Muz J, Sohn YH, Samlowski W, Weissler AM. Value of positive myocardial
Author Manuscript
technetium-99m-pyrophosphate scintigraphy in the noninvasive diagnosis of cardiac amyloidosis.

Am Heart J. 1982; 103:468–73. [PubMed: 6278906]
83. Falk RH, Lee VW, Rubinow A, Hood WB Jr, Cohen AS. Sensitivity of technetium-99m-
pyrophosphate scintigraphy in diagnosing cardiac amyloidosis. Am J Cardiol. 1983; 51:826–30.
[PubMed: 6299087]
84. Gertz MA, Brown ML, Hauser MF, Kyle RA. Utility of technetium Tc 99m pyrophosphate bone
scanning in cardiac amyloidosis. Arch Intern Med. 1987; 147:1039–44. [PubMed: 3036031]
85. Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P,
Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic diagnosis of cardiac
amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll
Cardiol. 2005; 46:1076–84. [PubMed: 16168294]
86. Rapezzi C, Guidalotti P, Salvi F, Riva L, Perugini E. Usefulness of 99mTc-DPD scintigraphy in
cardiac amyloidosis. J Am Coll Cardiol. 2008; 51:1509–10. author reply 1510. [PubMed:
18402909]
87. Rapezzi C, Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone O, Ferlini A, Salvi F, Gallo P,
Author Manuscript
Gagliardi C, Branzi A. Usefulness and limitations of 99mTc-3,3-diphosphono-1,2-

propanodicarboxylic acid scintigraphy in the aetiological diagnosis of amyloidotic
cardiomyopathy. Eur J Nucl Med Mol Imaging. 2011; 38:470–8. [PubMed: 21069320]
88. Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, Lane T, Whelan CJ, Lachmann
HJ, Gillmore JD, Hawkins PN, Wechalekar AD. Utility and limitations of 3,3-diphosphono-1,2-
propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging.
2014; 15:1289–98. [PubMed: 24939945]
89. Park MA, Padera RF, Belanger A, Dubey S, Hwang DH, Veeranna V, Falk RH, Di Carli MF,
Dorbala S. 18F-Florbetapir Binds Specifically to Myocardial Light Chain and Transthyretin
Amyloid Deposits: Autoradiography Study. Circ Cardiovasc Imaging. 2015; 8:e002954. [PubMed:
26259579]
90. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL,
Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castano A, Dorbala S, Johnson GB,
Glaudemans AW, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T,
Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt DF, Hazenberg BP, Rapezzi C,
Author Manuscript
Hawkins PN. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;

133:2404–12. [PubMed: 27143678]
91. Fine NM, Arruda-Olson AM, Dispenzieri A, Zeldenrust SR, Gertz MA, Kyle RA, Swiecicki PL,
Scott CG, Grogan M. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac
amyloidosis. Am J Cardiol. 2014; 113:1723–7. [PubMed: 24698461]
92. Satoskar AA, Efebera Y, Hasan A, Brodsky S, Nadasdy G, Dogan A, Nadasdy T. Strong
transthyretin immunostaining: potential pitfall in cardiac amyloid typing. Am J Surg Pathol. 2011;
35:1685–90. [PubMed: 21945954]

93. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet. 2016; 387:2641–54.
[PubMed: 26719234]
Author Manuscript
94. Bochtler T, Hegenbart U, Kunz C, Granzow M, Benner A, Seckinger A, Kimmich C, Goldschmidt

H, Ho AD, Hose D, Jauch A, Schonland SO. Translocation t(11;14) is associated with adverse
outcome in patients with newly diagnosed AL amyloidosis when treated with bortezomib-based
regimens. J Clin Oncol. 2015; 33:1371–8. [PubMed: 25779559]
95. Bochtler T, Hegenbart U, Kunz C, Benner A, Seckinger A, Dietrich S, Granzow M, Neben K,
Goldschmidt H, Ho AD, Hose D, Jauch A, Schonland SO. Gain of chromosome 1q21 is an
independent adverse prognostic factor in light chain amyloidosis patients treated with melphalan/
dexamethasone. Amyloid. 2015; 21:9–17.
96. Bochtler T, Hegenbart U, Kunz C, Benner A, Schonland SO. Reply to R. Warsame et al. J Clin
Oncol. 2015; 33:3976–7.
97. Warsame R, Kumar SK, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, Leung N, Dingli D, Lust
JA, Ketterling RP, Lin Y, Russell S, Hwa L, Kapoor P, Go RS, Zeldenrust SR, Kyle RA, Rajkumar
SV, Dispenzieri A. Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a
risk factor for cardiac involvement and for death. Blood Cancer J. 2015; 5:e310. [PubMed:
Author Manuscript
25933374]
98. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood. 2006; 108:2520–30. [PubMed:
16794250]
99. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin
Oncol. 2011; 29:1924–33. [PubMed: 21483018]
100. Dispenzieri A, Gertz MA, Buadi F. What do I need to know about immunoglobulin light chain
(AL) amyloidosis? Blood Rev. 2012; 26:137–54. [PubMed: 22537397]
101. Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM, Segal A, Ruberg F,
Meier-Ewert H, Andrea NT, Sloan JM, Finn KT, Doros G, Blade J, Skinner M. Outcome of AL
amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term
results in a series of 421 patients. Blood. 2011; 118:4346–52. [PubMed: 21828140]
102. Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL,
Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD,
Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive
patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014;
Author Manuscript
99:1479–85. [PubMed: 24859879]

103. Langer AL, Miao S, Mapara M, Radhakrishnan J, Maurer MS, Raza S, Mears JG, Solomon A,
Lentzsch S. Results of Phase I Study of Chimeric Fibril-Reactive Monoclonal Antibody 11–1F4
in Patients with AL Amyloidosis. Blood. 2015; 126:188–188.
104. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, Moon JC,
Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by
Antibodies to Serum Amyloid P Component. N Engl J Med. 2015; 373:1106–14. [PubMed:
26176329]
105. Comenzo RL. Out, Out--Making Amyloid’s Candle Briefer. N Engl J Med. 2015; 373:1167–9.
[PubMed: 26376140]
106. Gertz MALH, Comenzo RL, et al. Cardiac and renal biomarker responses in a phase 1/2 study of
NEOD001 in patients with AL amyloidosis and persistent organ dysfunction. Journal of Clinical
Oncology. 2015; 33:8514a.
107. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P,
Author Manuscript
Ronco P, Sanchorawala V, Sezer O, Solomon A, Grateau G. Definition of organ involvement and

treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from
the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April
2004. Am J Hematol. 2005; 79:319–28. [PubMed: 16044444]
108. Palladini G, Hegenbart U, Milani P, Kimmich C, Foli A, Ho AD, Vidus Rosin M, Albertini R,
Moratti R, Merlini G, Schonland S. A staging system for renal outcome and early markers of
renal response to chemotherapy in AL amyloidosis. Blood. 2014; 124:2325–32. [PubMed:
25115890]

109. Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating
physicians. Blood. 2013; 121:5124–30. [PubMed: 23670179]
Author Manuscript
110. Cohen AD, Comenzo RL. Systemic light-chain amyloidosis: advances in diagnosis, prognosis,
and therapy. Hematology Am Soc Hematol Educ Program. 2010; 2010:287–94. [PubMed:
21239808]
111. Shah G, Kaul E, Fallo S, Cossor F, Smith H, Sprague K, Klein A, Miller K, Comenzo R.
Bortezomib subcutaneous injection in combination regimens for myeloma or systemic light-chain
amyloidosis: a retrospective chart review of response rates and toxicity in newly diagnosed
patients. Clin Ther. 2013; 35:1614–20. [PubMed: 24075726]
112. Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins
P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib,
and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015; 126:612–5.
[PubMed: 25987656]
113. Kuhn DJ, Orlowski RZ, Bjorklund CC. Second Generation Proteasome Inhibitors: Carfilzomib
and Immunoproteasome-Specific Inhibitors (IPSIs). Current Cancer Drug Targets. 2011; 11:285–
295. [PubMed: 21247387]
Author Manuscript
114. Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E,
Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-
adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain
amyloidosis. Leukemia. 2013; 27:823–8. [PubMed: 23014566]
115. Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and
efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL
amyloidosis. Blood. 2007; 109:457–64. [PubMed: 16990593]
116. Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral
melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007;
110:787–8. [PubMed: 17606766]
117. Castano A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac
amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and
silencer drugs. Heart Fail Rev. 2015; 20:163–78. [PubMed: 25408161]
118. Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, Adams D, Suhr OB. Evolving
landscape in the management of transthyretin amyloidosis. Ann Med. 2015; 47:625–38.
Author Manuscript
[PubMed: 26611723]
119. Dubrey S, Ackermann E, Gillmore J. The transthyretin amyloidoses: advances in therapy.
Postgrad Med J. 2015; 91:439–48. [PubMed: 26048914]
120. Ericzon BG, Wilczek HE, Larsson M, Wijayatunga P, Stangou A, Pena JR, Furtado E, Barroso E,
Daniel J, Samuel D, Adam R, Karam V, Poterucha J, Lewis D, Ferraz-Neto BH, Cruz MW,
Munar-Ques M, Fabregat J, Ikeda S, Ando Y, Heaton N, Otto G, Suhr O. Liver Transplantation
for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?
Transplantation. 2015; 99:1847–54. [PubMed: 26308415]
121. Stangou AJ, Heaton ND, Hawkins PN. Transmission of systemic transthyretin amyloidosis by
means of domino liver transplantation. N Engl J Med. 2005; 352:2356. [PubMed: 15930432]
122. Gustafsson S, Ihse E, Henein MY, Westermark P, Lindqvist P, Suhr OB. Amyloid fibril
composition as a predictor of development of cardiomyopathy after liver transplantation for
hereditary transthyretin amyloidosis. Transplantation. 2012; 93:1017–23. [PubMed: 22395298]
123. Niemietz C, Chandhok G, Schmidt H. Therapeutic Oligonucleotides Targeting Liver Disease:
Author Manuscript
TTR Amyloidosis. Molecules. 2015; 20:17944–75. [PubMed: 26437390]

124. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S,
Tranter E, Munisamy M, Falzone R, Harrop J, Cehelsky J, Bettencourt BR, Geissler M, Butler
JS, Sehgal A, Meyers RE, Chen Q, Borland T, Hutabarat RM, Clausen VA, Alvarez R, Fitzgerald
K, Gamba-Vitalo C, Nochur SV, Vaishnaw AK, Sah DW, Gollob JA, Suhr OB. Safety and
efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013; 369:819–29.
[PubMed: 23984729]

125. Ackermann EJ, Guo S, Booten S, Alvarado L, Benson M, Hughes S, Monia BP. Clinical
development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy.
Author Manuscript
Amyloid. 2012; 19(Suppl 1):43–4. [PubMed: 22494066]

126. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD,
Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T,
Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ,
Diflunisal Trial C. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized
clinical trial. JAMA. 2013; 310:2658–67. [PubMed: 24368466]
127. Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Plante-Bordeneuve V, Lozeron P,
Suhr OB, Campistol JM, Conceicao IM, Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan
J, Packman J, Wilson A, Grogan DR. Tafamidis for transthyretin familial amyloid
polyneuropathy: a randomized, controlled trial. Neurology. 2012; 79:785–92. [PubMed:
22843282]
128. Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, Packman J, Powers ET,
Wiseman RL, Foss TR, Wilson IA, Kelly JW, Labaudiniere R. Tafamidis, a potent and selective
transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012;
109:9629–34. [PubMed: 22645360]
Author Manuscript
129. Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O’Hara C, Jasuja R, Trinkaus-Randall V, Liao R,
Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of
AL amyloidosis. Blood. 2011; 118:6610–7. [PubMed: 21998211]
130. Obici, LCA., Lozza, A., Palladini, G., Perlini, S., Gobbi, M., et al. A phase II study of
doxycycline plus tauroursodeoxycholic acid in transthyretin amyloidois. XIVth International
Symposium on Amyloidosis (ISA); 27 April – 1 May 2014;
131. Kristen AV, Lehrke S, Buss S, Mereles D, Steen H, Ehlermann P, Hardt S, Giannitsis E, Schreiner
R, Haberkorn U, Schnabel PA, Linke RP, Rocken C, Wanker EE, Dengler TJ, Altland K, Katus
HA. Green tea halts progression of cardiac transthyretin amyloidosis: an observational report.
Clin Res Cardiol. 2012; 101:805–13. [PubMed: 22584381]
132. aus dem Siepen F, Bauer R, Aurich M, Buss SJ, Steen H, Altland K, Katus HA, Kristen AV.
Green tea extract as a treatment for patients with wild-type transthyretin amyloidosis: an
observational study. Drug Des Devel Ther. 2015; 9:6319–25.
133. Coelho T, Maia LF, da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I,
Author Manuscript
Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Grogan DR. Long-term
effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol.
2013; 260:2802–14. [PubMed: 23974642]
134. Quarta CCF, Solomon RHSD, Suhr OB, Obici L, Perlini S, Lindqvist P, Koyama J, Sekijima Y,
Zeldenrust SR, Yamashita T, Horibata Y, Miller F, Gorevic P, Merlini G, Ando Y, Ikeda S,
Ruberg F, Berk JL. The prevalence of cardiac amyloidosis in familial amyloidotic
polyneuropathy with predominant neuropathy: The Diflunisal Trial. International Symposium on
Amyloidosis. 2014:88–89.
135. Lozeron P, Theaudin M, Mincheva Z, Ducot B, Lacroix C, Adams D. French Network for FAP.
Effect on disability and safety of Tafamidis in late onset of Met30 transthyretin familial amyloid
polyneuropathy. Eur J Neurol. 2013; 20:1539–45. [PubMed: 23834402]
136. Cho Y, Baranczak A, Helmke S, Teruya S, Horn EM, Maurer MS, Kelly JW. Personalized
medicine approach for optimizing the dose of tafamidis to potentially ameliorate wild-type
transthyretin amyloidosis (cardiomyopathy). Amyloid. 2015; 22:175–80. [PubMed: 26193961]
137. Hosenpud JD, DeMarco T, Frazier OH, Griffith BP, Uretsky BF, Menkis AH, O’Connell JB,
Author Manuscript
Olivari MT, Valantine HA. Progression of systemic disease and reduced long-term survival in
patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a
multicenter survey. Circulation. 1991; 84:III338–43. [PubMed: 1934428]
138. Maurer MS, Raina A, Hesdorffer C, Bijou R, Colombo P, Deng M, Drusin R, Haythe J, Horn E,
Lee SH, Marboe C, Naka Y, Schulman L, Scully B, Shapiro P, Prager K, Radhakrishnan J,
Restaino S, Mancini D. Cardiac transplantation using extended-donor criteria organs for systemic
amyloidosis complicated by heart failure. Transplantation. 2007; 83:539–45. [PubMed:
17353770]

139. Dey BR, Chung SS, Spitzer TR, Zheng H, Macgillivray TE, Seldin DC, McAfee S, Ballen K,
Attar E, Wang T, Shin J, Newton-Cheh C, Moore S, Sanchorawala V, Skinner M, Madsen JC,
Author Manuscript
Semigran MJ. Cardiac transplantation followed by dose-intensive melphalan and autologous

stem-cell transplantation for light chain amyloidosis and heart failure. Transplantation. 2010;
90:905–11. [PubMed: 20733534]
140. Davis MK, Kale P, Liedtke M, Schrier S, Arai S, Wheeler M, Lafayette R, Coakley T, Witteles
RM. Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. Am J
Transplant. 2015; 15:650–8. [PubMed: 25648766]
141. Davis MK, Lee PH, Witteles RM. Changing outcomes after heart transplantation in patients with
amyloid cardiomyopathy. J Heart Lung Transplant. 2015; 34:658–66. [PubMed: 25444369]
142. Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, Danziger-Isakov L,
Kirklin JK, Kirk R, Kushwaha SS, Lund LH, Potena L, Ross HJ, Taylor DO, Verschuuren EA,
Zuckermann A. International Society for Heart Lung Transplantation Infectious Diseases C,
International Society for Heart Lung Transplantation Pediatric Transplantation C, International
Society for Heart Lung Transplantation Heart F, Transplantation C. The 2016 International
Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year
update. J Heart Lung Transplant. 2016; 35:1–23. [PubMed: 26776864]
Author Manuscript
143. Gilstrap LNE, Maurer M, Feltrin G, Estep J, Witteles R, Zucker M, Baran D, Kushwaha S, Seldin
D, Semigran M. Multi-Center, International Registry of Cardiac Transplantation for Light Chain
(AL) and Transthyreitin (TTR) Amyloidosis, A [abstract]. Am J Transplant. 2013; 13(suppl 5)
144. Niehaus EGL, Maurer MS, Witteles R, Zucker M, Baran D, Estep J, Feltrin G, Stone JR, Patel J,
Seldin D, Semigran M. Outcomes from an international registry of cardiac transplantation for
light chain (AL) and transthyreitin (TTR) amyloidosis. Amyloid: Insoluble, but Solvable; XIVth
International Symposium on Amyloidosis. 2014
145. Topilsky Y, Pereira NL, Shah DK, Boilson B, Schirger JA, Kushwaha SS, Joyce LD, Park SJ. Left
ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy.
Circ Heart Fail. 2011; 4:266–75. [PubMed: 21303989]
146. Grupper A, Park SJ, Pereira NL, Schettle SD, Gerber Y, Topilsky Y, Edwards BS, Daly RC,
Stulak JM, Joyce LD, Kushwaha SS. Role of ventricular assist therapy for patients with heart
failure and restrictive physiology: Improving outcomes for a lethal disease. J Heart Lung
Transplant. 2015; 34:1042–9. [PubMed: 25940074]
Author Manuscript
147. Tabtabai S, Steiner J, Vaduganathan M, Stone J, Estep J, Witteles R, Giuseppe F, Zucker M,

Baran D, Seldin D, Patel J, Hanna M, Cordero-Reyes A, Selby V, Maurer M, Semigran MJ. The
Use of Circulatory Support While Awaiting Heart Transplant in Patients With AL and TTR:
Amyloidosis: A Report From iCCAT, the International Consortium for Cardiac Amyloid
Transplant. The Journal of Heart and Lung Transplantation. 34:S95–S96.
148. Burkhoff D, Maurer MS, Joseph SM, Rogers JG, Birati EY, Rame JE, Shah SJ. Left atrial
decompression pump for severe heart failure with preserved ejection fraction: theoretical and
clinical considerations. JACC Heart Fail. 2015; 3:275–82. [PubMed: 25770409]
Author Manuscript

Author Manuscript
Author Manuscript
Figure 1.
Mayo staging system for risk stratifying subjects with AL-CA in which one point is assigned
for each of the following: NT-pro-BNP ≥ 1800 pg/mL, Troponin T ≥0.025 ng/mL, and
difference in serum free light chains ≥ 18 mg/dL. Those with highest score have the worst
prognosis57 (Panel A).
Author Manuscript
Survival from the 3-month landmark of 300 patients with AL amyloidosis based on
hematologic response. The proportion of stage III patients was not significantly different
among the four hematologic response groups. CR, complete response; NR, no response; PR,
partial response; VGPR, very good partial response and py, person-year; 60 (Panel B).
Prognostic relevance of cardiac response and progression criteria showing survival from the
6-month landmark of 377 patients with immunoglobulin light chain (AL) amyloidosis and
baseline N-terminal natriuretic peptide type B (NT-proBNP)>650 ng/L according to NT-
proBNP response and progression60 (Panel C).
Survival according to NT-proBNP response in an ongoing phase 3 trial comparing
melphalan-dexamethasone with melphalan-bortezomib-dexamethasone (NCT01277016)61
(Panel D).
Author Manuscript

Author Manuscript
Author Manuscript
Author Manuscript
Figure 2.
Sequence of still images showing typical echocardiographic features of cardiac amyloidosis.
A: 2-D Parasternal long axis showing concentric left ventricular hypertrophy, bright
myocardium and left atrial dilatation. B: 2-D Parasternal short axis showing concentric left
ventricular hypertrophy and bright myocardium. C: 2-D Apical four chamber view showing
concentric left ventricular hypertrophy and biatrial dilatation D: Pulsed wave Doppler of
mitral inflow showing an increase in E/A ratio, normal E wave deceleration time but a
marked reduction in transmitral A wave velocity. E: Pulsed wave Doppler of pulmonary vein
inflow showing marked diastolic prominence and increased duration and peak velocity of
atrial reversal compared to the transmitral signal. F: Pulsed tissue Doppler of the lateral
mitral annulus showing marked reduction in apical systolic and diastolic velocities (normal
velocities being: >6 cm/sec and >8 cm/sec, respectively). Images courtesy of Professor
Author Manuscript
Elliott, University College London, UK

Author Manuscript
Author Manuscript
Author Manuscript
Figure 3.
Upper left panel: Subcostal 2D echocardiogram showing some the typical findings in
advanced cardiac amyloidosis. A: Biatrial enlargement, B: Thickened interatrial septum (and
valves), C: Thickening of RV free wall and D: Concentric LVH and hyperechoic myocardial
texture; Upper right panel: Apical 4-chamber peak systolic strain image illustrating
relatively well-preserved apical strain with significant basal impairment. This is seen in the
series of curves and the bull’s-eye color-coded strain image, Lower left panel: Patient with
atrial fibrillation and moderate to severely impaired LV function. Echocardiogram showed
increased myocardial density and concentric LVH with moderate aortic stenosis. Cardiac
MRI showed biventricular hypertrophy, moderate aortic stenosis, and diffuse fibrosis, in
Author Manuscript
excess of that expected for LVH and aortic valve disease. A) Early whole body planar DPD
image. B) 3h Delayed whole body planar image showing cardiac retention of racer and
reduced bony uptake; Perugini Grade 2. C), D), and E) 2 chamber, short axis, and 4 chamber
PSIR LGE cardiac MR images showing diffuse fibrosis. Images courtesy of Professor
Elliott, University College London, UK
Lower right panel: Fused Florbetapir PET/MR imaging. A) Native T1 map shows high
(>1400) values pre-contrast. B) ECV map, the ECV/interstitial space expansion is as high as

blood. C) LGE image- There is differential fibrosis, between the ‘core’ of the
Author Manuscript
interventricular septum and the epi- and endocardial borders (white vs red arrows) and also
in the lateral wall, which implies a non-uniform amyloid distribution. D) Fused Florbetapir
PET/MR uptake with a LV basal septal predominance. Images courtesy of Dr Leon
Menezes, University College London, UK
Author Manuscript
Author Manuscript
Author Manuscript

Author Manuscript
Author Manuscript
Figure 4.
Diagnostic algorithm for patients with suspected amyloid cardiomyopathy. The grading
system for bone scintigraphy is Grade 0 – absent cardiac uptake; Grade 1 – mild uptake less
than bone; Grade 2 - moderate uptake equal to bone; Grade 3 - high uptake greater than
bone. AApoA1 indicates apolipoprotein A-I; DPD, 3,3-diphosphono-1,2-
propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; and PYP,
Author Manuscript
pyrophosphate (from Gilmore, Circulation 201690)

Author Manuscript

Author Manuscript
Figure 5.
Author Manuscript
Disease modifying targets in TTR cardiac amyloidosis

Author Manuscript
Author Manuscript

Table 1
Red Flags and caveats in cardiac amyloidosis

Author Manuscript
• A high index of suspicion is mandatory for the recognition of CA (i.e. if you don’t think of it you won’t diagnose it)
• Cardiac amyloid should be suspected in any patient with heart failure, unexplained increased LV wall thickness and a non-dilated
LV
• In a patient with a suspicion for HCM, look for the infiltrative features that suggest amyloid such as pericardial effusion, AV
block, inter-atrial septal and valvular thickening and apical sparring.
• A distinctive sign of CA is the abnormal ratio between LV thickness and QRS voltages rather than low QRS voltages alone. The
absence of low QRS voltages doesn’t rule out a CA and up to 20% of subjects with CA can have electrocardiographic evidence of
left ventricular hypertrophy.
• In an elderly man with unexplained symmetric left ventricular hypertrophy, especially in the absence of hypertension, always
consider the possibility of ATTRwt-CA
• CA in an elderly patient with a monoclonal gammopathy is not necessarily due to AL: consider the possibility of ATTRwt and
MGUS
• Longitudinal LV function can be severely depressed despite a normal LVEF and the myocardial contraction fraction (MCF) is
often low suggesting reduced global myocardial shortening.
Author Manuscript
• Myocardial deformation is reduced in cardiac amyloidosis but the apex is generally spared
• On cardiac MRI both T1 signal abnormalities and marked extracellular volume expansion in patients with LV hypertrophy are
strongly suggestive of CA. LGE distribution is heterogeneous and sub-endocardial enhancement is not the only pattern.
• A history of bilateral carpal tunnel syndrome in a man with HCM-like phenotype on echo is highly suggestive of ATTRwt-CA
Author Manuscript
Author Manuscript

Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Table 2
Phenotypic findings in AL-CA and in the most frequent types of ATTR-CA
AL39, 47 ATTRwt34, 37, 39 Val122Ile34 Ile 68Leu31 Thr60Ala33

Maurer et al.
Median age at diagnosis (yr) 62 76 70 70 62
Males (%) 66% 95% 75% 75% 70%
Common ethnicity Variable Caucasian Afro-American Caribbean Caucasian (Italy) Caucasian (USA Ireland)
Cardiac referral route (%) 65 >80 >80 >80 30
IVS/PW (median values) 15/14 18/17 17/17 17/16 17/17
LVEF -% 56 50 50 50 53
Low QRS voltages (%) 45 33 45 30 16
Peripheral sensory-motor neuropathy (%) 10–20 <10 15 25% 54
History of carpal tunnel syndrome (%) <10 30–45 30 37 Unknown
Autonomic symptoms (%) 24 12–20 10 <10 75
Median survival (yr) Depends on stage 3.5 2–3 4–5 3.5
NTproBNP pg/L (median) ↑↑↑ ↑↑ ↑ ↑ ↑

Page 34
Table 3
Diagnostic Tests and Their Role in the Various Phases of Evaluation and Management of Cardiac Amyloidosis
Author Manuscript
Imaging and biomarkers of Cardiac Amyloidosis
Phase of work-up ECHO MRI* “Bone tracers” scintigraphy BNP
Suspicion +++ ++ +/− (TTR) ++

Early diagnosis +/− ++ ++ (TTR) +/−
Definite diagnosis +/− +/− +++ +/−
Etiologic diagnosis +/− +/− +++ (TTR) -
Functional evaluation +++ ++ + (MIBG) +/−
Prognostic stratification ++ + + +++
Amyloid burden - ++ +/− -
Response to therapy +/ +/− +/− +++ (AL)
Author Manuscript
*
T1 native, LGE ECV, TTR – useful for TTR amyloid, MIBG - iodine-131-meta-iodobenzylguanidine.
+++ = very useful, recommended, ++= useful, to be considered, += possibly useful
+/− = role uncertain, − = not useful.

Author Manuscript
Author Manuscript

Table 4
Recommendation for Evaluation of Extra-cardiac Organs in AL Amyloid Prior to OHT according to ISHLT
Author Manuscript
Guidelines
Organ System Screening Tests
Pulmonary Pulmonary function testing including arterial oximetry, diffusion capacity

CXR and CT to assess for interstitial disease, effusions
Thoracentesis may be necessary to differentiate amyloidosis from heart failure
Gastrointestinal Nutritional assessment including pre-albumin, albumin.

Assessment for bleeding by esophagogastroduodenoscopy, colonoscopy
Assessment of amyloid deposition on random biopsy
Assessment of intestinal motility with gastric-emptying studies
Hepatic Serum alkaline phosphatase and bilirubin.

An alkaline phosphatase >1.5 above upper limit of normal in the absence of congestion should prompt liver biopsy
to assess for portal and parenchymal amyloid deposition.
Author Manuscript
Renal Measured creatinine clearance or eGFR and 24-hour urinary protein excretion.
An eGFR or measured creatinine clearance <50 ml/min/1.73 m2 in the absence of decompensated heart failure or
urinary protein excretion >0.5 g/24 hours should prompt renal biopsy to assess the renal amyloid burden.
Coagulation Factor X and thrombin time

Patients with a severe(<25%) factor X functional deficiency have < 50% survival after ASCT
Adopted from J Heart Lung Transplant. 2016 Jan; 35(1):1–23).

Author Manuscript
Author Manuscript

nihms855616

Uploaded by

Copyright:

Available Formats

nihms855616

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

nihms855616

Uploaded by

Copyright:

Available Formats

HHS Public Access

Published in final edited form as:

Addressing Common Questions Encountered in the Diagnosis

3Tufts Medical Center

What forms of amyloidosis affect the heart?

Epidemiology and Delays in Diagnosis

Circulation. Author manuscript; available in PMC 2018 April 04.

How often is the diagnosis missed or delayed?

diagnosis of amyloidosis. Cardiologists were consulted more often than hematologists,

What are the impediments to early and accurate diagnosis?

In whom should one consider cardiac amyloid?

Circulation. Author manuscript; available in PMC 2018 April 04.

rupture of biceps tendon, unexplained neuropathic pain, orthostatic hypotension and a

Pathophysiology and Natural History

What is the natural history of ATTR cardiac amyloidosis?

Circulation. Author manuscript; available in PMC 2018 April 04.

physiologic derangements that include reduction in chamber capacitance, declines in

Diagnosing Cardiac Amyloidosis

Is there a lab test to diagnose CA?

Circulation. Author manuscript; available in PMC 2018 April 04.

dysfunction resulting in increased serum concentrations. Renal dysfunction affects kappa

Should everyone with TTR cardiac amyloidosis have gene sequencing?

conjunction with genetic counseling is recommended in cases in which hereditary TTR is

Do laboratory tests predict prognosis in CA?

Circulation. Author manuscript; available in PMC 2018 April 04.

decline in NT-pro-BNP response, defined as a decrease in NT-pro-BNP of >30% and >300

What is the role of imaging modalities in diagnosing CA?

advanced symptomatic disease. Analogous changes in RV diastolic function occur in the RV

Circulation. Author manuscript; available in PMC 2018 April 04.

apical sparing of longitudinal strain, representing an important diagnostic clue

What is the role of cardiac magnetic resonance imaging in diagnosis?

gadolinium enhancement in a non-coronary artery territory distribution with a dark blood

What is the role of myocardial scintigraphy in making a specific diagnosis?

Circulation. Author manuscript; available in PMC 2018 April 04.

Can PET be used to image and quantify amyloid?

When and how should tissue biopsy be undertaken?

How does one confirm the precursor protein causing amyloidosis?

Circulation. Author manuscript; available in PMC 2018 April 04.

Standard and Emerging Therapies for Cardiac Amyloidosis

is the key to improving prognosis in CA. Combination chemotherapy is effective in lowering

What are the goals of therapy for AL cardiac amyloidosis?

Circulation. Author manuscript; available in PMC 2018 April 04.

Circulation. Author manuscript; available in PMC 2018 April 04.

[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid (CPHPC),

What are the mechanisms of therapeutic efficacy (reduction in precursor protein/amyloid

Circulation. Author manuscript; available in PMC 2018 April 04.

Who is eligible for SCT?

What is the data on efficacy of therapies?

ATTR Cardiac Amyloidosis

Circulation. Author manuscript; available in PMC 2018 April 04.

dysfunction, fluid retention, and hypertension that may precipitate HF in vulnerable

What are the results of recent trials in TTR?

Circulation. Author manuscript; available in PMC 2018 April 04.

prevalence of presumptive CA in >50% of these FAP patients but analysis of

What therapies are in late phase development?

Cardiac Replacement therapy – Transplant and VAD

Circulation. Author manuscript; available in PMC 2018 April 04.

What additional testing is required for heart transplant evaluation?

How can I bridge my patient with advanced cardiac amyloid to an OHT?

required147. A theoretical analysis using a cardiovascular simulation of a novel micro-VAD