53
Cardiac Amyloidosis
FREDERICK L. RUBERG AND MATHEW S. MAURER
EPIDEMIOLOGY, 1052 Prognosis, 1054
Light Chain Amyloidosis, 1052
DIAGNOSIS, 1055
Transthyretin Amyloidosis, 1052
CLINICAL MANAGEMENT, 1058
PATHOPHYSIOLOGY, 1053
Supportive Non–Disease-­Modifying
CLINICAL FEATURES AND Therapies, 1058
PROGNOSIS, 1054 Disease-­Targeted Therapeutics, 1058
The systemic amyloidoses are a group of diseases characterized by the
extracellular deposition of insoluble, misfolded fibrillar proteins in the
form of β-­pleated sheets, resulting in organ dysfunction. First applied
to human disease by Rudolph Virchow in 1854, amyloid derives its
name from the Latin amylum or starch, because amyloid was initially
and erroneously thought to be composed of cellulose owing to a pos-
itive iodine-­staining reaction. Amyloid deposits evaluated by electron
microscopy demonstrated that amyloid fibrils are nonbranching pro-
tein structures, 80 to 100 Angstroms in width and of variable length.
They are resistant to proteolysis.Amyloid fibrils avidly bind to the histo-
logic stain Congo red imparting a hyaline pink appearance under light
microscopy, while under polarized light, fibrils reflect a characteristic
apple-­green birefringence.1 Precursor protein identification is essential
to define the type of amyloidosis, inform prognosis, and guide therapy.
The taxonomy is defined by abbreviating the type with an A (for amy-
loid) followed by a protein abbreviation.2 The two most common types
of amyloidosis that affect the heart are light chain (AL) amyloidosis
and transthyretin (ATTR) amyloidosis. ATTR amyloidosis is further sub-
classified by the sequence of the TTR gene, which resides on chro-
mosome 18. Hereditary or variant transthyretin amyloidosis (hATTR or
ATTRv) results from single nucleotide polymorphisms of the TTR gene
and are inherited in an autosomal dominant fashion. In ATTRv, amino
acid substitution results in a destabilization and misfolding process
that leads to amyloidogenesis. Historical nomenclature places a one-­
or three-­letter abbreviation for the normal amino acid at the position
of substitution in the protein followed by the substituted amino acid
(e.g., ATTR Val122Ile signifies isoleucine replacing valine at position
122 in the TTR amino acid sequence). More contemporary nomencla-
ture includes the 20-­amino acid signal peptide sequence in the count
of residues such that pVal142Ile (or pV142I) refers to the same variant
as Val122Ile. In contrast, wild-­type transthyretin amyloidosis (ATTRwt)
is a sporadic disease characterized by a normal TTR genetic sequence,
with unclear causes of TTR misfolding. Secondary amyloidosis (AA),
composed of serum amyloid A protein, can result from intense and
persistent systemic inflammation but rarely affects the heart. Finally,
uncommon genetic variants also known to affect the heart include
atrial natriuretic peptide (ANP), apolipoprotein A1 (ApoA1), fibrino-
gen (Afib), and gelsolin (Agel). This chapter will focus attention on AL
and ATTR amyloidosis, by far the most relevant types for the practicing
clinician.
EPIDEMIOLOGY
Light Chain Amyloidosis
Epidemiologic studies suggest that AL amyloidosis is a rare disease
with an annual incidence of approximately 1 per 100,000 individuals,
accounting for approximately 5000 new annual cases in the United
States. Cardiac involvement can be demonstrated in up to 70% of cases
of AL amyloidosis. Although AL amyloidosis can affect individuals
1052  
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CONCLUSION, 1060
REFERENCES, 1060
from the fourth decade of life onward, the prevalence of AL amyloi-
dosis increases with age, with a median age of diagnosis at 63 years,
and slight male predominance (between 55% and 65%). The current
estimated prevalence is 40 to 58 cases per million persons. AL amyloi-
dosis is related to, but distinct from, multiple myeloma and monoclonal
gammopathy of unknown significance (MGUS) (other clonal plasma
cell disorders). Among patients with MGUS, only a small percentage
will develop AL amyloidosis (1% overall, relative risk 8.8). Although
most patients with AL amyloidosis do not have multiple myeloma, up
to 10% to 15% of patients with multiple myeloma have coexisting AL
amyloidosis.3 
Transthyretin Amyloidosis
The epidemiology ATTR amyloidosis varies by type (ATTRwt and
ATTRv) and by specific variant, but conclusive data regarding popu-
lation incidence and prevalence are lacking. Autopsy studies have
demonstrated that up to 25% of decedents older than age 85 years have
demonstrable myocardial TTR amyloid deposits, with a prevalence that
increases with age, male sex, and is associated with a clinical diagno-
sis of heart failure.4 Contemporary imaging suggests that of older (>60
year) patients hospitalized with heart failure and preserved ejection
fraction with an increased left ventricular wall thickness, between 10%
and 15% of patients may have ATTRwt amyloidosis. Other studies of
older individuals with severe aortic stenosis demonstrate similar prev-
alence and male predilection for ATTRwt amyloidosis.5 Larger-scale
epidemiology studies designed to assess the prevalence of ATTRwt
amyloidosis are presently underway.
In contrast to ATTRwt, hATTR or ATTRv is caused by a genetic
mutation in the TTR gene. The TTR gene is composed of 4 exons
(127 amino acids) in which more than 100 mutations have been
described that can cause hereditary amyloidosis. Linked to a genetic
founder, each variant is endemic to a particular geographic region or
follows population migration patterns. Disease expression manifests
as a polyneuropathy or cardiomyopathy (previously termed familial
amyloidogenic polyneuropathy [FAP] or cardiomyopathy [FAC]).
Phenotypic penetrance varies widely by mutation and increases with
age (Table 53.1). The most common variant observed outside of the
United States is pVal50Met (Val30Met), endemic to Portugal, north-
ern Sweden, Japan, and Brazil. This variant causes predominantly a
polyneuropathy phenotype, but at a later age of onset causes amy-
loid cardiomyopathy. The pThr80Ala (Thr60Ala) variant first iden-
tified in a northern region of the Republic of Ireland, causes both
cardiomyopathy and polyneuropathy. Prevalence can approach 1%
in endemic areas but is very uncommon elsewhere in the world. By
far the most common TTR variant is pVal142Ile (Val122Ile), which
has been reproducibly identified in approximately 3.5% of self-­
identified Black persons in the United States.6 As a cause of ATTR
cardiomyopathy, this allele frequency translates into more than 1.6
million persons in the United States as carriers and therefore at risk
 1053
TABLE 53.1  Comparison of the Most Common Types of Cardiac Amyloidosis
FEATURES AL ATTR
53

Cardiac Amyloidosis
PRECURSOR LIGHT CHAIN—KAPPA VARIANT TTR
PROTEIN OR LAMBDA
CARDIOGENIC NEUROPATHIC/MIXED
SPECIFIC VAL122ILE LEU111MET ILE68LEU WILD-­TYPE
MUTATION (pV142I) (pL131M) (pI88L) THR60ALA (pT80A) VAL30MET (pV50M) TTR
Average age 63 (30–80) 72 (47–90) 48 (35–60) 71 (40–80) 66 (41–82) Early onset (30–50) 75 (50–>100)
(range)
Endemic,
neuropathic
Late onset (>50)—
nonendemic,
mixed phenotype
Gender (% male) 55%–60% 70% 64% 78% 60% 50% 90%
Race/ethnicity Not specific Black/Afro-­ Danish Italian Irish Portuguese, Not specific
Caribbean Swedish, Japanese
Cardiac ∼70% 100% 100% 96% 100% More common in 100%
involvement late onset
(%)
Fat pad biopsy 70%–80%* <50% <50% <50% <50% <50% <20%
Primary referral Hematology, Cardiology Cardiology Cardiology Neurology and Neurology and Cardiology
route cardiology, cardiology cardiology
nephrology,
dermatology
Extracardiac Nephrotic syndrome/ Autonomic Carpal Polyneuropathy Polyneuropathy Polyneuropathy Carpal tunnel
manifestations renal failure dysfunction tunnel (rare) syndrome
Autonomic Autonomic
syndrome
Autonomic dysfunction Carpal tunnel Carpal tunnel dysfunction dysfunction Lumbar spinal
syndrome stenosis
Purpura Lumbar spinal Carpal tunnel GI motility disorder
stenosis syndrome Biceps Tendon
Macroglossia Carpal tunnel
Rupture
syndrome
Carpal tunnel
syndrome
Median survival/ 1: Not reached (at 12 1: 54 months NR Median overall 1: 77 months Survival usually 1: 75 months
stage years) survival of >10 years and
2: 28.8 months 2: 54 months 2: 46 months
36 months improved with
2: 9.4 years
3: 17.7 months 3: 21 months liver transplant 3: 20 months
3: 4.3 years and tafamidis
3b: 1 year

AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; NAC, National Amyloidosis Centre, London, UK; NR, not reported.
*Dependent on extent of amyloid.

for ATTR cardiomyopathy. In addition, individuals of Hispanic/Latino
ancestry may also harbor this mutation which increases the risk of
developing heart failure nearly 50%. Unfortunately, among the vast
majority of allele carriers with heart failure, the diagnosis is delayed
or missed.7 That stated, the phenotypic penetrance of ATTR cardiomy-
opathy is unclear and depends upon the age of ascertainment, with
increasing penetrance with advancing age. Other TTR variants seen
world­wide that predominantly result in ATTR cardiac amyloidosis
include pIle88Leu (Ile68Leu, Italy) and pLeu131Met (Leu111Met,
Denmark).8  consisting of four identical subunits, synthesized in the liver, but also
PATHOPHYSIOLOGY
In AL amyloidosis, a dysregulated plasma cell clone produces kappa
or lambda immunoglobulin light chain fragments that have a propen-
sity to misfold, aggregate, and deposit in the myocardial interstitium.
Lambda light chain amyloidosis is more common than kappa, and
organ systems affected include the heart, kidneys, liver, nervous system
(including autonomic nervous system), gastrointestinal tract, and soft
tissues. The titer of light chain does not predict the site of target organ
deposition. Cardiac AL amyloidosis is viewed as a “toxic-­infiltrative”
cardiomyopathy involving two mechanisms: (1) interstitial and/or
perivascular amyloid fibril deposition leading to disruption of tissue
architecture, microvascular dysfunction with angina/ischemia, and
inhibition of contractile/relaxation functions and (2) direct toxicity to
cardiomyocytes through, in part, p38 mitogen-­activated protein kinase
(MAPK) signaling. Interstitial deposition results in a restrictive cardio-
myopathy and heart failure, and direct cellular toxicity is thought to
occur through induction of reactive oxygen species and apoptosis in
cardiomyocytes.3
Transthyretin, also known as prealbumin, is a tetrameric protein
by the choroid plexus and retinal pigmented epithelial cells. TTR
derives its name from its function as a circulating transporter of thy-
roid hormone and retinol (vitamin A). In hATTR, amino acid substitu-
tions alter the properties of the protein favoring tetramer dissociation
which is the rate-­limiting step in amyloid fibril formation. Monomers
then misfold and aggregate into amyloid fibrils that deposit in body
tissues with specific organ tropism. Precisely why native (i.e., geneti-
cally normal), wild-­type TTR becomes kinetically unstable and aggre-
gates is unclear, but the process definitively occurs with advancing
age (typically older than 60 years). Disease expression may also be
influenced by age-­related degradation in cellular systems that man-
age misfolded proteins. ATTR amyloidosis results in progressive myo-
cardial deposition (infiltrating between myocytes) and restrictive

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 1054
cardiomyopathy and/or a small fiber, length-­dependent peripheral
VI and autonomic neuropathy. Tissue tropism or organ system involve-
ment in ATTR amyloidosis is incompletely understood; however,
HEART FAILURE
there is developing evidence that the amyloid fibril composition may
play a role. Amyloid deposits composed of TTR fragments (type A
fibrils) are associated with later-­onset disease with cardiac involve-
ment in ATTRv and with ATTRwt, whereas full-­length TTR fibrils (type
B fibrils) in amyloid deposits correlate with earlier-­onset disease
without a strong cardiac phenotype.9  neuropathy, or both, with onset in the fifth decade.The common variant
CLINICAL FEATURES AND PROGNOSIS
There are various impediments that hinder the recognition of car-
diac amyloidosis by the cardiovascular clinician. First, the disease is
generally perceived to be rare and presents with clinical and imag-
ing features associated with more common conditions. Second,
cardiac amyloidosis was, until recently, an untreatable disease with
extremely poor prognosis lending credence to therapeutic nihilism.
Third and finally, the diagnostic approach required endomyocardial
biopsy, a procedure not appropriate in a scenario of low-­pretest like-
lihood or for widespread screening. Recent discoveries in epidemi-
ology, advancements in diagnostic imaging, and the development
of novel therapeutics have rendered each of these conceptions
invalid. Nevertheless, significant delays in disease recognition
persist. Among patients with ATTR amyloidosis, data demonstrate
increasing frequency of hospitalizations and visits for heart fail-
ure without disease recognition in the 3 years preceding ultimate
diagnosis.10
Although differing by precursor protein, the final common patho-
physiologic pathway of cardiac amyloidosis is one of myocardial
infiltration and progressive impairment in diastolic and systolic func-
tion that elicits symptoms of congestive heart failure. Left ventricular
ejection fraction (LVEF) is preserved in early stages of the disease,
while longitudinal contraction is impaired. Progressive infiltration
and/or direct myocyte toxicity subsequently results in decrement
in global left and right ventricular systolic function. Signs of heart
failure in more advanced disease become predominantly right-sided,
with lower extremity edema, ascites, and hepatic enlargement. For
this reason, the disease, particularly in early stages, is misrecognized
for more common wall-­thickening processes such as hypertensive
remodeling or hypertrophic cardiomyopathy (HCM). The electro-
cardiogram (ECG) classically demonstrates a low-­voltage pattern in
approximately 50% of patients with AL cardiac amyloidosis, while
inferior or anterior pseudoinfarcts are seen in greater than 70% of AL
cases. Low voltage is seen in only 25% to 40% of patients with ATTR,
while up to 15% can show evidence of left ventricular hypertrophy.
Conduction disease progressing to heart block is more commonly
a feature of ATTR amyloidosis. Atrial dysrhythmias, particular atrial
fibrillation (AF) and flutter, are seen in up to 40% to 60% of patients
with wtATTR amyloidosis at diagnosis and in up to 90% over time.
The risk of intracardiac thrombus is increased in all patients with car-
diac amyloidosis, even those in sinus rhythm, with stroke or systemic
embolization occurring in some patients. Although a low-­voltage pat-
tern itself can be attributable to other causes (pericardial effusion,
lung hyper-­expansion), integration of increased wall thickness seen
by echocardiography in the setting of a low-­voltage pattern (the mass
to voltage ratio), increases diagnostic accuracy.
One strategy to increase recognition involves identification of
other, noncardiac features of AL or ATTR amyloidosis in the context of
heart failure. Clinical features of AL amyloidosis are myriad and follow
organ system infiltration including renal (proteinuria, often nephrotic
range), soft tissue (macroglossia, carpal tunnel syndrome), gastrointes-
tinal (bleeding), or neurologic (peripheral or autonomic neuropathy).
Periorbital ecchymosis resulting from capillary fragility is considered
a pathognomonic feature of AL amyloidosis and is not seen in ATTR
amyloidosis. Hereditary ATTR amyloidosis presents as a small fiber,
length-­dependent peripheral neuropathy manifesting as parenthe-
sis, pain, or sensory loss on the hands and feet. However, autonomic
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neuropathy, most commonly manifesting as abnormal sweating, ortho-
static hypotension, gastrointestinal dysmotility, and erectile dysfunc-
tion, can also be observed in AL or ATTR. As noted previously, different
TTR variants present with either cardiomyopathy or neuropathy symp-
toms, or both. For example, the pVal50Met variant causes predom-
inantly neuropathy in early-­onset disease (third or fourth decade)
but cardiomyopathy and neuropathy in later onset (sixth or seventh
decade of life).The pThr80Ala variant causes either cardiomyopathy or
pVal142Ile affects individuals of West African origin generally in the
seventh decade of life, but nearly exclusively causes cardiomyopathy.
Rare ATTRv manifestations resulting from leptomeningeal involvement
include hydrocephalus and vitreous opacities.Wild-­type ATTR was pre-
viously held to be principally a cardiac-­restricted disease, although
soft tissue deposition manifesting as carpal tunnel syndrome, lumbar
spinal stenosis (ligamentum flavum thickening), and spontaneous ten-
don ruptures (biceps in particular) is now widely recognized. It is held
that the orthopedic/soft tissue manifestations of ATTRwt amyloidosis
precede the cardiac, often by many years. The presence of neuropa-
thy in ATTRwt is often difficult to disentangle for other age-­associated
neuropathies or comorbidities (including diabetes mellitus or alcohol
intake).
Prognosis
The prognosis of AL cardiac amyloidosis varies greatly depend-
ing upon two important contingencies: the stage of disease upon
diagnosis and, importantly, the response to chemotherapy directed
against the affected plasma cell clone. Prognosis is assessed by a
combination of biomarker risk assessment models and cardiac imag-
ing. Biomarker testing (Mayo or Boston University scoring systems)
involves measurement of brain natriuretic peptides (NT-­pro-­BNP or
BNP), cardiac troponin I or T, and direct measurement of lambda and
kappa light chain.11,12 Patients are classified into stages depending
upon the values of these biomarkers. Recent data demonstrate that
median survival for stage 2 patients (with either troponin or BNP
above threshold) is approximately 9.5 years, whereas for those with
advanced disease (stage 3b), median survival remains approximately
1 year. Imaging studies demonstrate that poor prognosis is also associ-
ated with lower echocardiographic stroke volume, increasing impair-
ment global longitudinal strain, increasingly severe cardiac magnetic
resonance imaging (CMR) late gadolinium enhancement (LGE),
and increasing CMR extracellular volume fraction (ECV).13 Each of
these imaging features is a marker of more advanced disease and is
strongly associated with cardiac biomarkers. Hematologic response
status and change in cardiac biomarkers with treatment also predict
prognosis. The attainment of a complete hematologic response is the
goal of all therapy and is strongly associated with improved survival.
A reduction in BNP or NT-­pro BNP of greater than 30% from base-
line is also indicative of a cardiac response and is associated with
improved prognosis.
The prognosis of ATTR amyloidosis differs between hereditary and
wild-­type genotype. Similar to AL amyloidosis, staging systems using
cardiac biomarkers and renal function have been developed to inform
prognosis. Despite the larger population of affected patients as com-
pared with AL, data limited to case series estimate median survival
in ATTRwt amyloidosis to be approximately 3.5 years and for ATTRv
amyloidosis pVal142Ile to be approximately 2.5 years from diagnosis.
However, as in AL, prognosis depends upon stage of disease at diagno-
sis. Using a combination of NT-­proBNP and troponin T (Mayo system)
or NT-­proBNP and estimated glomerular filtration rate (eGFR, National
Amyloidosis Centre system), data demonstrate that for ATTRwt median
survival following diagnosis ranges from 5 to 7 years for stage 1 (early
stage) to 2 to 3 years for stage 3 (advanced stage).14,15 It is important to
emphasize that the natural history studies currently available do not
account for contemporary TTR-­specific therapies which can extend
survival. Like AL, imaging also informs prognosis with increasing CMR
LGE and ECV and worsening global longitudinal strain associated with
impaired survival. 
 1055

Features that should raise suspicion for cardiac amyloidosis

• Increased wall thickness without obvious cause 53
• HFpEF with concomitant right heart failure (+JVP, hepatomegaly, edema)

Cardiac Amyloidosis
• HFpEF with normal/low blood pressure particularly in males >60 years of age
• Discordance of wall thickness and electrocardiographic voltage
• History of carpal tunnel syndrome, lumbar spinal stenosis, or spontaneous biceps tendon rupture
• Paradoxical low flow low gradient aortic stenosis
• Diffuse late gadolinium enhancement or increased extracellular volume by cardiac MRI
• Apical preservation on longitudinal strain echocardiography
• Natriuretic peptides elevated out of proportion to clinical syndrome
• Persistently elevated troponin in the absence of acute coronary syndrome or other cause

Evaluate for AL cardiac amyloidosis by the presence of monoclonal protein:

• Abnormal serum kappa/lambda free light chain ratio, and
• Immunofixation of serum and urine
Obtain biomarkers for staging including NTproBNP (or BNP), Troponin T
(or Troponin I) and eGFR

Abnormal plasma Normal plasma

cell testing results cell testing results

Referral to hematology for MGUS Bone scintigraphy

evaluation and consideration of bone available?
marrow biopsy, and
• Biopsy of clinically involved organ or fat
pad (if fat pad negative, biopsy of
clinically involved organ should be Yes No
pursued)
• Congo red staining, and
• Identification of precursor protein Noninvasive evaluation Endomyocardial biopsy with
with mass spectroscopy (preferred) with PYP, DPD, or HMDP • Congo red staining, and
or by immunohistochemistry (Grade 2/3) with SPECT • Identification of precursor
confirmation of myocardial protein with mass
tracer retention spectroscopy (preferred)
Positive Negative or IHC

Diagnostic myocardial No myocardial

AL, ATTR, or other Cardiac uptake update + –
amyloidosis amyloidosis
unlikely
ATTR Cardiac ATTR Cardiac
Cardiac amyloidosis Cardiac amyloidosis
amyloidosis unlikely amyloidosis unlikely

TTR Gene TTR Gene

sequencing sequencing

Variant Normal Variant Normal

ATTRv ATTRwt ATTRv ATTRwt

FIGURE 53.1  Algorithm for cardiac amyloidosis diagnosis. Accurate diagnosis of cardiac amyloidosis can be made by tissue biopsy or by noninvasive methods (bone-­seeking
nuclear tracers) following exclusion of monoclonal protein. Note appropriate testing for monoclonal protein involves serum-­free light chain assay and serum and urine immu-
nofixation electrophoresis (not serum protein electrophoresis). Nuclear imaging with bone-­seeking radiotracers (PYP, DPD, or HMDP) can be performed concurrent to mono-
clonal protein assessment to afford additional information. DPD, 99mTc-3,3-diphosphono-1,2-propanedicarboxylic acid; HMDP, 99mTc-hydhydroxyl-methylene-diphosphonate;
MGUS, monoclonal gammpopathy of unknown significance; PYP, 99mTc-pyrophosphate.

DIAGNOSIS
The critical step to enable a diagnosis of cardiac amyloidosis is clini-
cal suspicion forged, in part, by attention to associated signs/symptoms
and reassessment of changes in clinical features previously attributed
to other processes. Examples of the latter point include intolerance
to beta blockade (a feature of restrictive filling), intolerance to
angiotensin-­converting enzyme (ACE) inhibitors, angiotensin receptor
blockers (ARBs), or angiotensin receptor/neprilysin inhibitors (ARNIs),
or a reduced requirement for antihypertensives. Heightened awareness
in specific affected populations is also essential, such as severe aortic
stenosis, particularly the low-­flow, low-­gradient phenotype. In addition,
several “red flag” features have been proposed including extreme left
ventricle (LV) wall thickening (>15 mm), discordant ECG voltage as
predicted from wall thickness, orthopedic/soft tissue manifestations,
and characteristic patterns on imaging testing.16 A clinical algorithm to
guide the approach toward accurate diagnosis of cardiac amyloidosis
can be found in Figure 53.1.
Diagnosis of amyloidosis classically requires tissue biopsy with
Congo red (or Thioflavin) staining and precursor protein identifica-
tion by immunohistochemistry and/or mass spectrometry. In the case
of AL amyloidosis, a tissue biopsy is required to establish the diagno-
sis. Establishment of cardiac amyloidosis, however, does not require
an endomyocardial biopsy, as supportive evidence from imaging

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 1056
and biomarker testing afford a very high predictive value for cardiac
VI involvement.17 Furthermore, it is the severity of cardiac impairment in
AL that defines treatment regimens, rather than the binary adjudica-
HEART FAILURE
tion of cardiac involvement. Unlike AL, ATTR amyloidosis can now be
accurately diagnosed with imaging testing (nuclear scintigraphy) com-
bined with testing for light chain amyloidosis, when performed in the
proper clinical context.
BIOMARKERS
Persistent and unexplained elevation in cardiac biomarkers, includ-
ing the aforementioned troponins and natriuretic peptides, are hall-
mark features of cardiac amyloidosis but are nonspecific. Although
candidates have been proposed, there are no specific biomarkers yet
reported that can definitively identify cardiac amyloidosis. In AL, abnor-
mal increase in either lambda (more common) or kappa free light chain
with abnormal ratio, and/or identification of a monoclonal band on
immunofixation electrophoresis is indicative of a plasma cell dyscrasia.
In the proper context, these findings can increase suspicion for AL but
are not diagnostic. Furthermore, it is common in the setting of chronic
kidney disease to observe a kappa predominance with abnormal free
light chain ratio, confusing interpretation. In addition, MGUS incidence
increases with age and plasma cell testing abnormalities can be seen in
up to 40% to 50% of patients with ATTR amyloidosis.18 Thus hemato-
logic consultation is indispensable in unclear scenarios. A serum protein
electrophoresis (SPEP) is insensitive for identifying AL amyloidosis and
should not be obtained without subsequent immunofixation. Emerging
data suggest that lower prealbumin (TTR) concentration may identify
patients with ATTRv amyloidosis and can inform prognosis in ATTRwt.
Similarly, the TTR ligand retinol-­binding protein 4 (RBP4), also appears to
identify ATTRv pVal142Ile amyloidosis, although its capacity to predict
prognosis has not been well explored.19  tion of ATTR amyloidosis has increased. Nuclear techniques have noted
IMAGING
Cardiac imaging plays an essential role in the diagnostic pathway for
cardiac amyloidosis identification (Table 53.2). Recently published mul-
tisocietal consensus recommendations for the acquisition, analysis, and
reporting of imaging in cardiac amyloidosis have conferred important
standardization.20,21 Echocardiography is indispensable (see also Chap-
ter 16). Findings include increased biventricular thickening (above the
upper limit of normal for age and sex but often ≥12 mm for the LV),
dilated atria, interatrial septal thickening, valvular thickening, evidence
of right ventricular thickening, pericardial effusion, dilated inferior vena
cava, diastolic dysfunction, and increased left atrial pressures (see also
Fig. 16.31 and Video 16.28). Global measures of systolic function are
generally preserved in early to midstage disease; however, segmental
variation in systolic function is evident early. Global longitudinal strain
is often reduced and in specific, basal segments often are hypokinetic
relative to apical segments. This distinctive pattern is described as “api-
cal sparing” (Fig. 53. 2) and can be quantified with longitudinal systolic
strain deformational imaging with an approximate apical/basal ratio of
greater than 2 or apical/basal+mid strain greater than 0.7 (relative apical
sparing). Increased LVEF/global longitudinal strain ratio greater than 4
is also suggestive of amyloid cardiomyopathy.22 Echocardiographic fea-
tures, although raising suspicion of amyloid cardiomyopathy, are not in
themselves diagnostic. Another echocardiographic parameter that has
utility in identifying cardiac amyloidosis and predicting clinical outcomes
is the myocardial contraction fraction (MCF, ratio of LV stroke volume to
myocardial wall volume).
CMR imaging (see Chapter 19) with LGE affords the capacity to
visualize the extracellular space expansion that results from amyloid
fibril deposition.23 As in echocardiography, AL and ATTR patterns over-
lap; thus, although useful for adjudication of amyloid from nonamy-
loid, the specific type cannot be reliably identified. Cardiac amyloidosis
demonstrates diffuse enhancement throughout the myocardial seg-
ments, either in a global subendocardial or transmural pattern, often
with atrial involvement. The inability to suppress (“null”) the myo-
cardium in cine-­inversion recovery (Look-Locker) sequences is a com-
mon feature. LGE CMR is approximately 85% to 90% sensitive and
specific for identification of amyloid cardiomyopathy in patients with
clinically suspected disease. As extracellular amyloid fibril deposition
increases, the interstitial space between myocytes expands. Parametric
T1 mapping demonstrates increased native (noncontrast) T1 and ECV
is typically greater than 0.40. One distinct advantage of CMR over
other imaging modalities is its capacity to differentiate other diseases
that may mimic the amyloid cardiomyopathy phenotype (e.g., HCM,
Fabry disease).
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Although bone avid radiotracers have been used for myocar-
dial infarction imaging for more than 40 years, it is now recognized
that the tracers 99mTc-­pyrophosphate (PYP), 99mTc-­3,3-­diphosphono-­
1,2-­propanedicarboxylic acid (DPD), and 99mTc-­hydroxyl-­methylene-­
diphosphonate (HMDP) can detect cardiac amyloidosis and differentiate
ATTR from AL (see Figs. 18.34, 18.35, and eFig. 18.7). Using a sim-
ple semiquantitative methodology (the Perugini score), cardiac tracer
uptake is compared with rib with grade 0 (no uptake) to grade 3 (car-
diac uptake greater than rib) and determined either after 1 or 3 hours
of tracer incubation. Alternatively, ATTR cardiac amyloidosis can be
differentiated from AL using 99mTc PYP (the tracer available in United
States) by a heart to contralateral lung (H/CL) quantitative uptake ratio
of greater than 1.5 from a region of interest drawn over the heart and
contralateral chest after a 1 hour of tracer incubation. Single-­photon
emission computed tomography (SPECT) is required to confirm myocar-
dial (and not blood pool) tracer uptake. A large international collabora-
tion using a cohort of biopsy-­proven AL and ATTR cardiac amyloidosis
patients demonstrated that nuclear tracers provided 100% specificity
when grade 2 or 3 uptake was seen in the absence of a monoclonal
protein by serum or urine in individuals with heart failure and typical
echocardiographic or CMR features of amyloidosis.24 In addition, a mul-
ticenter study validated these results with 99mTc-­PYP and additionally
showed H/CL ratio greater than 1.6 conferred worse survival.25 It is
essential that lab testing excludes evidence of a monoclonal gammopa-
thy in conjunction with nuclear imaging to properly interpret the testing
results. For these reasons, ATTR cardiac amyloidosis can now be diag-
nosed using bone avid tracers and blood testing without the need for
confirmatory cardiac tissue biopsy when properly applied. It is appropri-
ate to note that there remains some disagreement in the optimal timing
of imaging following tracer injection. That stated, with the adoption,
awareness, and growing availability of this imaging technique, recogni-
ATTR amyloidosis in 16% of patients with aortic stenosis undergoing
transcatheter aortic valve replacement and 5% of patients with pre-
sumed HCM, with 26% of those referred for HCM older than 80 years
of age having cardiac amyloidosis. Although nuclear techniques hold
great promise as a means to screen for ATTR amyloidosis when applied
in the proper clinical context, endomyocardial biopsy remains neces-
sary in cases of demonstrated monoclonal gammopathy or in cases of
equivocal tracer uptake and high clinical suspicion. Although not widely
available, positron emission tomography (PET) tracers specific for amy-
loid deposits (florbetapir, florbetaben, 11C-­Pittsburgh-­B) also identify
cardiac amyloidosis and may prove clinically useful in the future. 
BIOPSY
Endomyocardial biopsy remains the “gold standard” for diagnosis of car-
diac amyloidosis and is considered 100% sensitive and specific if biopsy
specimens are collected from multiple sites (four or more are recom-
mended). Definitive typing for the precursor protein must be determined
by immunohistochemistry or via the more preferred, laser dissection with
tandem mass spectrometry (LC MS/MS) analysis. Endomyocardial biopsy
carries a small but notable risk of perforation, tamponade, or access site
complications and as such is reserved for confirmatory testing in sus-
pected cases wherein imaging testing is inconclusive (or isolated AL car-
diac amyloidosis). Abdominal fat aspirate with Congo red staining can
be helpful; however, sensitivity for ATTRwt is low (only approximately
20%) and a negative result should not dissuade continued evaluation.26
Biopsies of other sites (e.g., gastrointestinal), have widely reported sensi-
tivities/specificities, and as with fat aspirate, a negative result should not
dissuade further testing in scenarios of high clinical suspicion. 
GENOTYPING
Genotyping of TTR is a final critical step in the ATTR amyloidosis diag-
nostic algorithm because it has implications for treatment as well as
raises the possibility of gene inheritance for first-­degree relatives. One
approach proposed as means to achieve amyloidosis screening involves
widespread genotyping. Such an approach can accurately identify
known variants associated with ATTR amyloidosis, although it is import-
ant to note that clinical penetrance is unclear and varies with age and
family history. This has been most widely explored for the pVal142Ile
genotype. Although data clearly demonstrate that the inheritance of
the pVal142Ile allele increases the risk of heart failure,7 evidence from
other studies suggest that the allele does not necessarily result in imag-
ing evidence of ATTR amyloidosis.27 Furthermore, a genotyping-­only
approach will fail to identify ATTRwt, the most common type of cardiac
amyloidosis. Although rare, the possibility of non-­TTR variants including
gelsolin, AApoA1, A2, and AFib (fibrinogen) should be considered in
the presence of defined cardiac amyloidosis and a strong family history
with normal TTR gene sequence.  
 1057
TABLE 53.2  Comparison of Diagnostic Imaging Modalities in Cardiac Amyloidosis
FEATURE ECHOCARDIOGRAPHY MRI BONE SCINTIGRAPHY
53

Clinical clues Pericardial or pleural effusions,
thick right ventricle, small
LV cavity, intra-­atrial septal
thickening, and impaired
global longitudinal strain
characteristically with sparing of
the apex
Relative cost $ $$
Specialized expertise required for No
interpretation
Exposure to ionizing radiation No
Cardiac devices affect image quality No
Can identify nonamyloid causes of Yes (valvular disease, HCM,
LV thickening diastolic function) though
amyloid CM may also be present
Distinguish AL and ATTR No
Markers of worse prognosis Lower stroke volume, greater
regional variation in global
longitudinal strain, worse global
longitudinal strain, lower MCF,
low EF (late phase)
AL, Amyloidogenic light chain; ApoA1, apolipoprotein A1; EF, ejection fraction; H/CL, heart to contralateral lung; HCM, hypertrophic cardiomyopathy; LV, left ventricle; MCF,
myocardial contraction fraction; SPECT, Single-­photon emission computed tomography.
*In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.
Elevated native T1,
increased extracellular
volume fraction, late
gadolinium enhancement
in any pattern, abnormal
gadolinium kinetics
Yes
No
Yes
Yes (infiltrative disease, HCM)
No
Late gadolinium
enhancement, higher
extracellular volume
fraction, higher native T1
Cardiac Amyloidosis
Diagnostic for transthyretin amyloid
cardiomyopathy (ATTR-­CM) if normal light
chain assays and grade 2/3 cardiac uptake with
confirmation of myocardial retention by SPECT
False positives due to AL cardiac amyloidosis,
previous myocardial infarction, diffuse myocardial
scarring, overlying previous rib fracture, blood
pool, hydroxychloroquine toxicity, and unusual
forms of cardiac amyloidosis (ApoA1)
$
No
Yes
No
No
Yes*
H/CL ratio ≥1.6 at 1 hr

V
I aVR V1 V4

5
II aVL V2 V5

III aVF V3 V6 10

II

V1

A B
V5

Peak-systolic
longitudinal strain (%)
Anterior

–2.7

30
–9.5
–3.0 –4.3

–13.1 –21.9 –5.3

Septal

Lateral

–17.6 –25.5
–26.3 10.8

–3.9 16.1 –4.0

–3.0 –4.7
–7.0

–30
–7.4

C Inferior
D E
FIGURE 53.2  Electrocardiographic and imaging findings in cardiac amyloidosis. A 77-­year-­old male with dyspnea and palpitations presents for evaluation. A, Electrocardio-
gram (ECG) demonstrates atrial fibrillation, with low voltage in the limb leads and a pseudoinfarct pattern in the anterior leads. B, Still-­frame image from parasternal long-axis
echocardiogram illustrating severely increased wall thickness (19 mm) discordant from ECG low-­voltage findings. C, Echocardiographic global longitudinal strain polar map
showing apical-sparing pattern. D, Cardiac MR with phase-sensitive inversion recovery late gadolinium enhancement (PSIR-­LGE) imaging demonstrating diffuse subendocardial
and transmural enhancement. E, Planar Tc99m pyrophosphate (PYP) image showing grade 3 tracer uptake, confirmed by single-­photon emission computed tomography (SPECT),
with a heart to contralateral chest ratio of 1.7. Endomyocardial biopsy confirmed ATTRwt amyloidosis.

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 1058
CLINICAL MANAGEMENT
VI
Supportive Non–Disease-­Modifying Therapies
HEART FAILURE
In contrast to other etiologies of heart failure, the evidence basis under-
lying clinical management in cardiac amyloidosis, although increas-
ing, remains sparse. As such, management strategies are largely drawn
from smaller, nonrandomized, observational case series. That being
stated, aforementioned consensus recommendations for imaging
and a recently reported AHA Scientific Statement distilled available
evidence into coherent recommendations to guide clinical manage-
ment.28 In general, the approach to a patient with cardiac amyloido-
sis involves treatment of the underlying cause (chemotherapy for AL,
TTR-­ directed therapies for ATTR) and concurrent management of
heart failure, arrhythmia, and concomitant symptoms. As such, the gen-
eral principles underlying non–disease-­modifying therapy for cardiac
amyloidosis include symptom management, maintenance of euvole-
mia, avoidance of polypharmacy (particularly in elderly patients),
avoidance of medications that may cause symptomatic hypotension,
implantation of electrical devices (pacemakers, defibrillators), and
consideration of advanced circulatory support/transplant for refrac-
tory heart failure in a minority of patients.
MANAGEMENT OF HEART FAILURE
Maintenance of euvolemia and optimization of perfusion in patients
with cardiac amyloidosis can be a distinct challenge. Perturbations of fill-
ing hemodynamics from diastolic dysfunction with impairment of stroke
volume (restriction), renal dysfunction from intrinsic renal disease, poor
perfusion, or the cardiorenal syndrome, and in some individuals, con-
current autonomic dysfunction from amyloid neuropathy renders a very
narrow range of tolerable circulating volume. Bioavailable loop diuret-
ics and aldosterone antagonists are the preferred first-­line agents with
frequent dose adjustments to address changes in volume status that
may result from concomitant chemotherapies for AL amyloidosis, such
as steroids. Patients with orthostasis from poor vascular tone owing to
impaired autonomic function may require the alpha-­agonist midodrine
to maintain adequate systolic blood pressure.
Evidence-­based therapies that have proven beneficial in other
causes of heart failure including ACE inhibitors, ARBs, ARNIs, and
beta blockers are generally poorly tolerated in patients with advanced
cardiac amyloidosis owing to fixed stroke volume and impaired hemo-
dynamic compensatory mechanisms. Lower doses are often useful to
manage hypertension or AF heart rate in earlier stage patients. Non-
dihydropyridine calcium channel blockers (CCBs) are generally con-
traindicated in cardiac amyloidosis because they can bind amyloid
fibrils (demonstrated in AL only), and worsen heart failure through
heart-rate slowing, negative inotropy, and potentiation of conduction
block. Interestingly, the affinity of TTR amyloid fibrils for various bone-
seeking radiotracers is thought to be calcium related, thereby suggest-
ing a potential mechanism for increased binding of CCBs to amyloid
fibrils. Dihydropyridine CCBs may be useful as adjunctive agents for
blood pressure management, particularly in the context of renal dys-
function, although potentiation of lower-extremity edema may limit
application. Although an in vitro study demonstrated that isolated
AL amyloid fibrils bind digoxin with high affinity, digoxin has been
recently reconsidered if used cautiously as adjunctive management in
AF rate control.29  by contemporary therapies.28
ARRHYTHMIA MANAGEMENT
Atrial dysrhythmias, particularly AF and atrial flutter, are extremely com-
mon in ATTR amyloidosis and less commonly seen in AL amyloidosis.
Management involves anticoagulation to prevent thromboembolism
and rate control, and if exacerbating symptoms of heart failure, rhythm
control is also appropriate. As with maintenance of euvolemia, heart
rate control can also be challenging to optimize because both tachy-
cardia and bradycardia are poorly tolerated, resulting from restrictive
hemodynamics. Maintaining sinus rhythm and the atrial contribution to
ventricular filling in cardiac amyloidosis may be less important because
many patients have significantly reduced atrial mechanical function,
reducing the atrial contribution to ventricular filling. Regularization
and slowing of heart rate likely provide equal or greater benefit. The
stroke risk among patients with AF and cardiac amyloidosis is exceed-
ingly high because of blood stasis and elevated pressures, and atrial
amyloid deposition may potentiate thrombosis. Left atrial appendage
thrombosis has been observed in the context of normal sinus rhythm
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and after therapeutic anticoagulation, underscoring the imperative to
perform transesophageal echocardiography prior to attempts at resto-
ration of sinus rhythm by cardioversion.30 Heparins, vitamin K antago-
nists, or direct-acting oral anticoagulants are all effective in reducing
thromboembolic risk and should be considered as indefinite therapy
with minimal interruption. As specified in recent American College of
Cardiology/American Heart Association/Heart Rhythm Society (ACC/
AHA/HRS) recommendations, agents that may be used for rhythm con-
trol include amiodarone (most commonly) and dofetilide.29 Data sup-
porting the use of catheter ablation in cardiac amyloidosis are limited. In
early-­stage patients, cavotricuspid isthmus ablation may help to main-
tain sinus rhythm in the setting of atrial flutter, while pulmonary venous
isolation procedures are generally less effective at controlling AF than in
nonamyloid populations.
In ATTR in particular, deposits of amyloid fibrils infiltrate the conduc-
tion system, with a significant percentage of patients requiring per-
manent pacing. Pacing following AV junctional ablation for refractory
AF management can also be considered. Biventricular pacing can be
considered for patients with preexisting reduced LVEF. The routine use
of automatic implantable cardioverter-­defibrillators (ICDs) in patients
with cardiac amyloidosis is debatable as sudden cardiac death related
to ventricular tachycardia (VT) or ventricular fibrillation (VF) is relatively
uncommon and mortality typically results from pulseless electrical
activity. If anticipated survival is less than 1 year, then practice guide-
lines do not recommend ICD placement for the primary prevention of
sudden cardiac death.29 Device implantation for primary prevention
is debatable, although ICD placement after aborted sudden death or
sustained VT/VF is less controversial provided survival is expected to
exceed 1 year. 
ADVANCED CIRCULATORY SUPPORT AND ORGAN
TRANSPLANTATION
Selected patients with advanced heart failure may qualify for orthot-
opic heart transplantation (OHT) and/or mechanical circulatory support
(MCS) after careful assessment for the extent of systemic involvement.
Acceptable outcomes have been reported in small series of carefully
selected patients with AL that underwent OHT followed by treatment
for AL (typically stem cell transplant–based regimens but more recently
targeted anti-­plasma cell therapy alone). Similarly, outcomes after OHT
in ATTR patients with wild-­type or cardiac-­restricted variant disease
(typically pVal142Ile) do not differ from those transplanted for other
nonamyloid indications. Patients with ATTRv can be treated with OHT
followed by TTR-­specific pharmacotherapies to slow allograft TTR depo-
sition. MCS with left ventricular assist devices (LVADs) or total artificial
heart has been reported as a bridge to transplant in a small number of
highly selected patients, but outcomes are worse in part because of
small ventricular chamber size leading to suction events and, in the case
of LVAD, concomitant right heart failure.
The majority of circulating TTR protein (95%) is produced by the liver.
Orthotopic liver transplantation (OLT) replaces amyloidogenic mutant
TTR with wild-­type TTR and theoretically arrests amyloid formation. Prior
to contemporary pharmaceutical therapies, OLT was the only available
TTR-­specific treatment for ATTRv amyloidosis. The treatment is largely
effective among patients without demonstrable cardiac involvement;
however, among those with cardiac amyloidosis, there is still a risk of
progressive cardiac deposition after isolated OLT owing to continued
wild-­type TTR deposition upon the template of previous amyloid depos-
its. Combined OHT and OLT was formerly a strategy in ATTRv disease
with a neuropathic TTR variant but has been largely rendered obsolete
  
Disease-­Targeted Therapeutics
Light Chain Amyloidosis
The ultimate goal of chemotherapy for AL amyloidosis is elimination
of the plasma cell clone that produces the amyloidogenic light chain.
Arresting amyloid production reverses disease progression, preserves
organ function, and enhances survival. Chemotherapeutics are drawn
from the armamentarium of agents developed for multiple myeloma.
The objective is attainment of a complete hematologic response
(CR) defined as normalization of the involved free light chain and
light chain ratio, elimination of a monoclonal band by immunofixa-
tion electrophoresis, and normalization of the bone marrow plasma
cell population. Degrees of hematologic response are defined by the
proportion of light chain reduction from complete, very good partial,
 1059
TABLE 53.3  Therapies for Amyloidogenic Transthyretin Amyloidosis
COMMON, SERIOUS
53
MECHANISM OR POTENTIAL SIDE CONCOMITANT

Cardiac Amyloidosis
DRUG NAME OF ACTION INDICATION ROUTE DOSE EFFECTS THERAPY MONITORING COST
Patisiran Silencer Neuropathy IV 0.3 mg/kg q3 Infusion-related With IV infusion: None $450,000
weeks up reactions annual list
• IV steroids
to 30 mg price
Vitamin A deficiency
• Acetaminophen
$345,000
• IV H1 blocker average
• IV H2 blocker effective net
annual price
• D
 aily vitamin A
supplements
Inotersen Silencer Neuropathy SQ 284 mg Thrombocytopenia/ Daily vitamin A Weekly platelet $450,000
weekly glomerulonephritis, supplements counts. annual list
requiring testing price
Every 2 weeks
before treatment and
measures $345,000
monitoring during
of serum average
therapy
creatinine, effective net
Infusion-site reactions, eGFR annual price
fever urinalysis,
and urine
Vitamin A deficiency
protein to
creatinine
ratio
Tafamidis Stabilizer Neuropathy/ Oral 20 mg once Side effects were None None €100,000 per
meglumine Cardio­ a day less common than year
myopathy with placebo in
80 mg once $225,000 per
cardiomyopathy
a day year
Tafamidis Stabilizer Cardio-­ Oral 61 mg once Unknown None None $225,000 per
free salt myopathy a day year
Diflunisal Stabilizer Neuropathy/ Oral 250 mg PO Related to NSAID Proton pump inhibitor Monitor renal $300-­500 per
Cardio-­ twice a properties: function, year
myopathy day platelet
• Bleeding
count,
• Hypertension hemoglobin
• Fluid retention 1–2 weeks
after
• Renal dysfunction initiation and
then every 3
months

eGFR, Estimated glomerular filtration rate; hATTR, Hereditary transthyretin amyloidosis; NSAID, nonsteroidal antiinflammatory drug.

partial, and no response. As noted earlier, the biomarker scoring sys-
tems developed for prognosis are also used to follow response to treat-
ment. First-­line strategies vary by institutional experience and must be
individualized to a particular patient. In appropriately selected patients
managed at highly specialized referral centers with extensive experi-
ence, high-­dose melphalan-­based chemotherapy coupled with autol-
ogous stem cell transplant (HDM/SCT) can be applied as a means to
rapidly reduce the light chain concentration. In such centers, a com-
plete or very good partial response can be induced in approximately
60% of patients with a peritransplant mortality less than 2% while dura-
ble, long-­term complete response (>15 years) can be achieved.31 Eligi-
bility for HDM/SCT is defined by various clinical parameters including
(but not limited to) LVEF, pulmonary function, blood pressure, and per-
formance status.32 For those not eligible for HDM/SCT, contemporary
advances in chemotherapy offer many alternative and highly effective
options. Regimens include combinations of drugs such as proteasome
inhibitors, immune modulators, and most recently, monoclonal anti-
bodies. In specific, a monoclonal antibody targeting the CD38-­receptor
(daratumumab), developed for the treatment of patients with relapsed
multiple myeloma, has produced a rapid and profound hematologic
response with minimal toxicity.33 This agent, which can be delivered
subcutaneously, results in robust hematologic and organ responses
with an acceptable safety profile.34 Daratumumab is the first and only
agent specifically approved by FDA for AL amyloidosis and is now
considered first line therapy in combination with cytoxan, bortizimib,
and dexamthasone. 
Transthyretin Amyloidosis
There are numerous pharmacologic strategies developed to amelio-
rate ATTR amyloidosis, including TTR silencing or knockdown, TTR
stabilization, and TTR amyloid fibril disruption/extraction (Table 53.3).
Presently, there are three U.S. Food and Drug Administration (FDA)-­
approved therapies for ATTR amyloidosis including the TTR silencers
patisiran and inotersen, and the TTR stabilizer tafamidis, with additional
novel agents in clinical trials. In addition, the FDA-­approved nonsteroi-
dal antiinflammatory drug (NSAID) diflunisal has been repurposed
for ATTR amyloidosis treatment and demonstrated efficacy in smaller,
nonrandomized, retrospective studies.
TTR Stabilizers
As a therapeutic class, TTR stabilizers are orally available small
molecules that bind to TTR and inhibit its dissociation and subse-
quent amyloid fibril formation. Tafamidis is a benzoxazole deriva-
tive lacking NSAID activity specifically engineered to bind to the
thyroxine-­binding sites of TTR with high affinity and selectivity, stabi-
lizing the tetramer and slowing dissociation and subsequent aggre-
gation. The efficacy of tafamidis in ATTR cardiac amyloidosis was
demonstrated in the phase III clinical study Amyloid Transthyretin

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 1060
Amyloidosis Cardiomyopathy Trial (ATTR-­ ACT), where treatment
VI resulted in lower all-­cause mortality and reduction in cardiovas-
cular hospitalizations.35 Treatment also resulted in a lower rate of
HEART FAILURE
decline in distance for the 6-­minute walk test and in the Kansas City
Cardiomyopathy Questionnaire (KCCQ-­OS) as compared with con-
trols. Tafamidis was approved in May of 2019 as the only therapeutic
approved for ATTRwt cardiac amyloidosis. Given its extremely high
initial cost, the cost-­effectiveness of the therapy was deemed poor
despite the efficacy.36
Diflunisal is an NSAID that, like tafamidis, binds to the TTR tetramer
at the thyroxine-binding site, kinetically stabilizing it from dissocia-
tion. Used off-­label in a phase III study of patients with ATTRv amy-
loidosis, diflunisal at a reduced dose of 250 mg twice daily improved
symptoms of amyloid polyneuropathy.37 Retrospective studies have
demonstrated the safety of diflunisal in selected patients with eGFR
greater than 45 mL/min and efficacy as determined by improved
echocardiographic markers of decline with increased survival in
treated patients. Diflunisal has emerged as a cost-­effective alternative
therapy in selected patients with careful monitoring of volume status
and renal function.4 An additional stabilizer with a separate molecu-
lar TTR-binding site (acoramidis, or AG10) is currently in a phase III
clinical trial with promising preliminary results from smaller phase
II studies.38  7. Damrauer SM, Chaudhary K, Cho JH, et al. Association of the V122I hereditary transthyretin
TTR Silencers
TTR protein silencers hold great promise to halt or even reverse ATTR
cardiac amyloidosis by significantly reducing circulating TTR. Pati-
siran is a small interfering RNA (siRNA) delivered intravenously that
specifically targets hepatic TTR messenger RNA (mRNA) to elicit
degradation and subsequent inhibition of TTR protein translation.
Administered every 3 weeks, the drug reduces circulating TTR protein
levels by approximately 90%. Patisiran must be co-­administered with
corticosteroids and histamine receptor blockers to blunt immune/
histamine response. Efficacy of patisiran in ATTRv amyloidosis with
polyneuropathy was demonstrated in the phase III APOLLO trial,
where patients randomized to active drug experienced improved neu-
ropathy (as measured by the modified neuropathy impairment score,
mNIS+7) and quality of life.39 More than 50% of patients in APOLLO
had cardiac amyloid involvement, and in a cardiac subgroup analysis
with wall thickness greater than 13 mm, patisiran resulted in signifi-
cant improvements in NT-­proBNP,LV wall thickness, global longitudinal
strain, and gait speed compared with placebo.40 Patisiran was approved
by the FDA for ATTRv amyloidosis and polyneuropathy, with or with-
out cardiomyopathy. Patisiran and another RNA interfering therapeutic,
vutrisiran (delivered subcutaneously every 3 months) are presently
being evaluated in phase III trials of cardiac amyloidosis patients that
includes those with ATTRwt.
The 2′-­O-­methoxyethyl–modified antisense oligonucleotide inot-
ersen is a short synthetic RNA that binds and inhibits translation
of target hepatic TTR mRNA, thereby suppressing expression. Effi-
cacy of inotersen in ATTRv amyloidosis in ameliorating clinically
assessed polyneuropathy and quality of life was demonstrated in
the NEURO-­TTR study.41 Inotersen received FDA approval for ATTRv
amyloid polyneuropathy with or without cardiomyopathy (as in
patisiran). Both agents were deemed not cost-­ effective in cost-­
effective analyses based on current U.S. prices.42 Given observed
toxicities of thrombocytopenia and glomerulonephritis (both 3%),
inotersen was approved with a Risk Evaluation and Mitigation Strat-
egy (REMS) that includes weekly monitoring of platelet counts and
every 2-­week monitoring of renal function and urinary protein. A
small, open-­label study of inotersen in patients with ATTR cardiomy-
opathy demonstrated stabilization of LV wall thickness, mass, global
longitudinal strain, and functional capacity.43 Ongoing clinical trials
of inotersen and the related ligand-­conjugated antisense oligonu-
cleotide (LICA, trial CADRIO-­TTRansform) in ATTR cardiac amyloi-
dosis, including ATTRwt, are ongoing. A promising, early-stage report
of a clustered regularly interspaced short palindromic repeats and
associated Cas9 endonuclease (CRISPR-Cas9) based therapeutic
(NTLA-2001) affords the potential for permanent silencing of TTR
expression.44  mumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020;135:1541–1547.
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November 11, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.
CONCLUSION
The diagnostic and therapeutic landscape for cardiac amyloidosis
has dramatically changed over the recent past. A disease that formerly
was conceived as uncommon and untreatable is now increasingly
recognized with available therapies that dramatically extend survival
and mitigate symptoms. Advances in noninvasive diagnosis coupled
with concurrent demonstration of efficacy and approval of specific
therapies has shifted cardiac amyloidosis from a rarely encountered
and untreatable “zebra,” to a condition that cardiovascular clinicians
should consider in daily practice.
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