JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 68, NO.

12, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.06.053

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

AL (Light-Chain) Cardiac Amyloidosis

A Review of Diagnosis and Therapy

Rodney H. Falk, MD,a Kevin M. Alexander, MD,a Ronglih Liao, PHD,a Sharmila Dorbala, MD, MPHa,b

JACC JOURNAL CME

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Method of Participation and Receipt of CME Certificate
To obtain credit for JACC CME, you must:
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suggest a diagnosis of light-chain (AL) cardiac amyloidosis; 2) promptly
initiate and complete a diagnostic workup for cardiac amyloidosis,
including a timely referral to a hematologist if AL amyloidosis is sus-
pected; and 3) prescribe appropriate heart failure therapy for cardiac
amyloidosis, avoiding drugs that are poorly tolerated in AL amyloidosis
and providing appropriate diuretic therapy adjustments in a patient un-
dergoing chemotherapy.
CME Editor Disclosure: JACC CME Editor Ragavendra R. Baliga, MD,
FACC, has reported that he has no financial relationships or interests to
disclose.
Author Disclosures: This study was supported in part by the Demarest
Lloyd Jr. Foundation, The Friends of Burt Glazov Cardiac Amyloidosis
Fund, and the Harold Grinspoon Charitable Foundation. Dr. Falk receives
funds for consulting from Ionis Pharmaceuticals and Alnylam Pharma-
ceuticals; and research support from GlaxoSmithKline. All other authors
have reported that they have no relationships relevant to the contents of
this paper to disclose.
Medium of Participation: Print (article only); online (article and quiz).
CME Term of Approval

CME Objective for This Article: On completion of this activity the learner Issue Date: September 20, 2016
should be able to: 1) recognize the clinical and non invasive features that Expiration Date: September 19, 2017

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aBrigham and Women’s Hospital Cardiac Amyloidosis Program, Harvard Medical School and Department of Medicine,
Section of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts; and the bDepartment of Radiology, Division of
Nuclear Medicine and Molecular Imaging, Harvard Medical School, Boston, Massachusetts. This study was supported in part by
the Demarest Lloyd Jr. Foundation, The Friends of Burt Glazov Cardiac Amyloidosis Fund, and the Harold Grinspoon Charitable
Foundation. Dr. Falk receives funds for consulting from Ionis Pharmaceuticals and Alnylam Pharmaceuticals; and research
support from GlaxoSmithKline. All other authors have reported that they have no relationships relevant to the contents of this
paper to disclose.

Manuscript received June 9, 2016; accepted June 14, 2016.

1324 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

AL (Light-Chain) Cardiac Amyloidosis

A Review of Diagnosis and Therapy
Rodney H. Falk, MD,a Kevin M. Alexander, MD,a Ronglih Liao, PHD,a Sharmila Dorbala, MD, MPHa,b

ABSTRACT

The amyloidoses are a group of protein-folding disorders in which $1 organ is infiltrated by proteinaceous deposits known
as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is
determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis)
carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease.
The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel
approaches to the diagnosis and treatment of cardiac amyloidosis are discussed, with particular reference to AL
amyloidosis in the heart. (J Am Coll Cardiol 2016;68:1323–41) © 2016 by the American College of Cardiology Foundation.

C ardiac amyloidosis is a condition in which

the extracellular space of the heart is
expanded by an amorphous, fibrillar pro-
teinaceous material known as amyloid (Figure 1).
The nonbranching fibrils of amyloid are composed
not only of fragments of the precursor protein, but
also contain proteoglycans and serum amyloid P
(SAP). They are generally extremely resistant to
degradation, although evidence suggests that amy-
loid does slowly resorb from the body once fibrillo-
genesis has been halted (1,2). Amyloid can be
formed from a large number of different precursor
proteins (Table 1), but the most common forms that
produce amyloid that affects the heart are
immunoglobulin-derived light chains and transthyre-
tin (TTR; previously called prealbumin). Rarely, sec-
ondary amyloid may cause cardiac involvement, but
this is an uncommon manifestation of a type of amy-
loid rarely seen in Western countries. TTR is a trans-
port protein of thyroid hormone and retinol
(vitamin A); hence, the name, transthyretin.
TTR-derived amyloid may be formed from wild-type
(normal) TTR or from a mutant form, of which >80
amyloidogenic mutations have been described. Pre-
cise definition of the precursor protein causing amy-
loid deposition is essential because the different
forms of amyloidosis have differing clinical courses
and completely different therapies. TTR amyloidosis
(ATTR) has recently been reviewed in detail in the
Journal (3), and therefore, this review concentrates
on light-chain (AL) amyloidosis as it affects the heart,
addressing TTR amyloidosis predominantly when it
differs from AL amyloidosis.
It is important to recognize that cardiac amyloidosis
is part of a systemic disease, and is not an isolated
condition. In AL amyloidosis, renal, neural, and/or
dermatologic involvement often coexists with heart
involvement. Less commonly, symptomatic hepatic
and gastrointestinal infiltration may occur. Patients
with familial amyloidosis (mutant TTR amyloidosis
[ATTRm]) often have a phenotype that is deter-
mined to a large degree by the specific mutation,
with neuropathy-predominant, cardiac-predominant,
and mixed phenotypes tending to run in families,
although exceptions do exist. Wild-type TTR
amyloidosis (ATTRwt), in which the precursor protein
is structurally normal TTR, almost invariably presents
as a clinically isolated cardiomyopathy. However, the
condition was formerly named senile systemic
amyloidosis because of the subclinical involvement of
other organs noted at autopsy (most commonly, the
lungs and gastrointestinal tract) and a high prevalence
of carpal tunnel syndrome due to amyloid infiltration.
Until recently, cardiac amyloidosis was viewed as a
rare condition, often only diagnosed at autopsy, and
was considered untreatable when diagnosed during
life. Enormous advances have been made over the last
decade, both in diagnosis and treatment of cardiac
amyloidosis, along with a recognition that the condi-
tion is more common than previously believed. This
review gives a detailed overview of cardiac amyloid-
osis with an emphasis on AL amyloidosis, describes a
diagnostic approach to the various types, and dis-
cusses novel and experimental treatments.
AL amyloidosis is a hematologic disorder of plasma
cells closely related to, but generally distinct from,
multiple myeloma. It is caused by the proliferation of
an abnormal clone of plasma cells that overproduce
lambda, or less commonly, kappa light chains. In
multiple myeloma, most of the cellular components
JACC VOL. 68, NO. 12, 2016 Falk et al. 1325
SEPTEMBER 20, 2016:1323–41 AL Amyloidosis and the Heart

of the bone marrow may consist of plasma cells, and exact prevalence of clinically isolated AL ABBREVIATIONS

in overt disease, this results in bone lesions, anemia, cardiac amyloidosis is unknown, it is likely AND ACRONYMS

hypercalcemia, and/or renal dysfunction (4). In that is has been underestimated in the past,
AL amyloidosis = light-chain
contrast to myeloma, most patients with AL due to the rapid progression to death in un- amyloidosis
amyloidosis have #20% of plasma cells in the diagnosed patients. The increasingly sophis-
ATTR amyloidosis =
marrow, and the manifestations of the disease are ticated diagnostic tools currently used in transthyretin amyloidosis
due to the formation of amyloid from the abnormal heart failure appear to be leading to earlier ATTRm amyloidosis = mutant
circulating free light chains (5). Approximately 5% to diagnosis, thereby possibly lessening missed transthyretin amyloidosis

10% of patients with AL amyloidosis will have evi- diagnoses. ATTRwt = wild-type

dence of overt multiple myeloma, and a similar pro- The importance of early diagnosis of AL transthyretin amyloidosis

portion of multiple myeloma patients will have AL cardiac amyloidosis cannot be stressed CMR = cardiac magnetic
resonance
amyloidosis. It is estimated that AL amyloidosis is strongly enough. Untreated, the median sur-
CPHPC = (R)-1-[6-[(R)-2-
approximately one-tenth as common as multiple vival from onset of heart failure is approxi-
carboxy-pyrrolidin-1-yl]-6-
myeloma, with an estimated annual age-adjusted mately 6 months (6), but modern therapies oxo-hexanoyl]pyrrolidine-2-
incidence in the United States of 10.5 cases per can put the disease into a prolonged remis- carboxylic acid

million person-years (6). sion and extend life by many years (7). There DPD = 2,3-dicarboxypropane-1,

AL amyloidosis is a multiorgan disease, although 1 is a slight male predominance of AL cardiac 1-diphosphonate

organ system usually predominates. It most amyloidosis, and the disease generally pre- ECG = electrocardiography

commonly affects the kidney, resulting in nephrotic sents from the fifth to seventh decade, LGE = late gadolinium
enhancement
syndrome, with clinical cardiac involvement being although it may occur at all ages from the
the second most common presenting manifestation. fourth decade onward. LV = left ventricular

Other organ systems that may be involved include the MGUS = monoclonal protein of
unknown significance
peripheral and autonomic nervous system, the CLINICAL ASPECTS. All types of cardiac
NT-proBNP = N-terminal pro–
vasculature, the liver and gastrointestinal tract, and amyloidosis share a common pathological
B-type natriuretic peptide
the soft tissues. Cerebral involvement does not occur aspect, namely, the extracellular deposition
SAP = serum amyloid
in AL amyloidosis. Previous reviews of amyloidosis of amyloid in the heart. The different forms P component
have often stressed that cardiac involvement in AL of amyloid are generally indistinguishable by
TcPYP = technetium
amyloidosis almost always occurs in the setting of light microscopy, and by the time heart fail- pyrophosphate
another significant organ involvement, and that iso- ure is present, extensive amyloid is easily TTR = transthyretin
lated cardiac disease is present in <5% of cases. In our visible (Figure 1). The amyloid deposits
experience, this is probably not true. Although the expand the extracellular space and stiffen the heart

F I G U R E 1 Endomyocardial Biopsy

Staining with hematoxylin and eosin (left) and sulfated Alcian blue (right). Note that the amyloid deposits are extensive and extracellular,
compressing the cardiomyocytes. This leads to myocardial dysfunction, due to both stiffening of the extracellular space and direct myocyte
damage. The inset on the left shows an electron microscope image of an amyloid deposit, demonstrating the nonbranching fibrils. The inset on
the right shows amyloid surrounding a small vessel. This can result in angina with normal-appearing epicardial coronary arteries seen on
coronary angiography. (see text for more details). Courtesy of Robert Padera, MD, Brigham and Women’s Hospital, Boston, Massachusetts.
1326 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

T A B L E 1 Overview of the Common Forms of Amyloidosis That May Affect the Heart

Amyloid
Nomenclature Precursor Protein Age Range, yrs Sex Clinical Clues Laboratory Abnormalities

AL Light chains 50þ Either Multiorgan involvement. Elevated serum free lambda or
Periorbital bruising or kappa, with abnormal ratio.
macroglossia are almost Monoclonal spike in serum
pathognomonic of AL in and/or urine. Suppressed
setting of typical MRI or immunoglobulins.
echocardiogram. Proteinuria.
Severe hypotension with ACE
inhibitors.
ATTRwt Wild-type (normal) 65þ Marked male History of carpal tunnel syndrome No specific abnormalities.
transthyretin predominance, 5-10 yrs earlier, with no (Normal free light chain
>15:1 other organ involvement. values, no proteinuria)
ATTRm Mutant transthyretin 40þ (mutation Either, slight male African-American/Caribbean origin No specific abnormalities on
dependent). In predominance. (for V122I TTR variant). routine testing.
V122I, the Genetic testing reveals mutation
common African- in TTR molecule
American variant,
usual age of
clinical onset is
60-65 yrs.
AA (Secondary) Serum amyloid A May occur in 20s–30s Either Underlying chronic inflammatory High ESR/CRP. Proteinuria.
(an acute phase protein) upward with disease.
severe Hepatomegaly, splenomegaly.
inflammatory Usually no cardiac involvement,
disease. but in rare cases may be severe

ACE ¼ angiotensin-converting enzyme; CMR ¼ cardiac magnetic resonance; CRP ¼ C-reactive protein; ECG ¼ electrocardiogram; ESR ¼ erythrocyte sedimentation rate; LBBB ¼ left bundle branch block;
TTR ¼ transthyretin.

without producing compensatory dilation, which re-
sults in a restrictive pathophysiology involving both
ventricles (Figure 2). Atrial amyloid infiltration is
almost always present and frequently causes atrial
contractile dysfunction. Amyloid deposition also
occurs on valves and perivascularly. Although the
precise type cannot be distinguished from the pattern
of amyloid deposition, it appears that there are
different deposition patterns in TTR and AL amyloid-
osis, with a predominance of diffuse peri-cellular,

F I G U R E 2 Autopsy Specimen of the Heart From a Patient Who Died of Cardiac Amyloidosis

(Left) Biatrial dilation with thickened atrial septum and extensive thickening of the left ventricle (and, to a lesser degree, the right ventricle),
due to amyloid infiltration. (Right) Close-up view of the atrium, showing the waxy, irregular surface due to amyloid deposition. Atrial infiltration
leads to atrial dysfunction, and the irregular endocardial deposits can form a nidus for thrombus formation, accounting for the high prevalence
of atrial thrombi in amyloid cardiomyopathy. Courtesy of Robert Padera, MD, Brigham and Women’s Hospital, Boston, Massachusetts.
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
endocardial, and arterial and/or arteriolar deposits
in AL amyloidosis and nodular deposits in ATTR (8).
The pathophysiology of cardiac AL amyloidosis
differs from that of ATTR amyloidosis. Specifically,
although both diseases are associated with extracel-
lular fibril deposition within the myocardium, which
leads to passive myocardial restriction and dysfunc-
tion, clinical observations have suggested that the
severity of heart failure in AL amyloidosis is more
severe than in TTR amyloidosis, despite higher left
ventricular (LV) mass in the latter (9). This observa-
tion, coupled with the discordance between clinical
improvement and lack of change in standard echo-
cardiographic parameters after successful hema-
tologic treatment, led to the suggestion that AL
amyloidosis might have both toxic and infiltrative
components (10).
Shortly after this observation was made, amyloi-
dogenic light-chain toxicity was demonstrated in an
isolated, perfused heart model—a case of “bedside to
bench” research (11). Not all light chains are car-
diotoxic, and LV dysfunction is not seen in multiple
myeloma without amyloidosis, nor in AL amyloidosis
without myocardial infiltration, which suggests that
amyloid infiltration of the heart is required before
light-chain cardiotoxicity can be clinically manifest.
Unpublished observations by one of the authors
(R.H.F.) has also suggested that, although most AL
amyloidosis patients with evidence of cardiac
amyloidosis have heart failure, there is a small group
who develop marked amyloid infiltration with mini-
mal heart failure, similar to many ATTR amyloidosis
patients. It is postulated that the amyloidogenic light
chain in these patients does not have cardiotoxic
properties.
CELLULAR ABNORMALITIES. The past decade has
seen considerable activity in elucidating the mecha-
nism of the rapidly progressive nature of AL
amyloidosis of the heart. Following the observation
that amyloidogenic light chains produce cardiac
dysfunction in the isolated heart (12), it was demon-
strated that physiological levels of amyloidogenic
light chains caused an increase in cellular reactive
oxygen species and up-regulation of heme oxygenase
in rat cardiomyocytes, with associated impairment in
contractility and relaxation (12). This toxic effect was
blocked by antioxidants. In a series of experiments,
a cascade effect of toxic light chains from patients
with amyloidosis was demonstrated at a subcellular
level. The initial response was lysosomal dysfunc-
tion, which led to impaired autophagy and culmi-
nated in elevated reactive oxygen species, cellular
dysfunction, impaired calcium homeostasis, and
Falk et al. 1327
AL Amyloidosis and the Heart
F I G U R E 3 Postulated Mechanisms Leading to Progressive Heart Failure in
AL Amyloidosis
Amyloid precursor
Amyloid fibers protein and/or
oligomers
Structural damage Proteotoxicity
Increased cardiac and Stress kinase activation
vascular stiffness Lysosomal dysfunction
Impaired contraction Defective autophagy
and relaxation ROS
Disturbed electrical Cellular dysfunction/
conductance impaired calcium
homeostasis
Defected
mitochondrial
function
Cell death
Infiltration of the myocardium causes physical cellular damage and restrictive patho-
physiology, whereas circulating cardiotoxic light chains produce cellular damage through
various pathways (see text for details). In other forms of cardiac amyloid, such as TTR, the
sole (or overwhelmingly predominant) mechanism of cardiac dysfunction is the infiltrative
component. ROS ¼ reactive oxygen species; other abbreviations as in Figure 1.
eventually, cell death (13). It was postulated that
impaired autophagy, the failure to clear breakdown
products in cells, led to this cascade, and sirolimus, a
potent enhancer of both autophagosome formation
and clearance, prevented the cardiomyocyte toxicity
induced by amyloidogenic light chains (13). Sirolimus
is in clinical use to prevent post-transplantation
rejection, but clinical studies of its use in amyloid
cardiomyopathy have not yet been performed.
There have been several other investigations into
potential mechanisms by which AL amyloidosis of
the heart causes such significant clinical dysfunc-
tion. Amyloidogenic light chains were found to have
a significant effect on vascular reactivity, both in
human adipose tissue and coronary arterioles (14).
Light chain–induced apoptosis and necrotic injury
were attributable to oxidative stress, and both
impaired arteriolar reactivity and cellular damage
were largely abolished using a potent antioxidant.
This vascular dysfunction, seen in vitro in human
arterioles, has a parallel in AL amyloidosis patients,
in whom early endothelial dysfunction has been
1328 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

F I G U R E 4 Two Noncardiac Clinical Clues to the Presence of AL Amyloidosis

(Left) Small periorbital spontaneous bruise in a man with cardiomyopathy due to AL amyloidosis. He had had recurrent spontaneous bruising of
the eyes for >1 year and dyspnea for 6 months before the diagnosis was recognized. The combination of spontaneous periorbital bruising
and heart failure is virtually pathognomonic of AL amyloidosis cardiomyopathy. (Right) Macroglossia in a 65-year-old woman with AL
amyloidosis of the heart and soft tissues. Note the prominent tooth indentations on the tongue. She had seen 2 ear, nose, and throat specialists
because of her large tongue. Despite the fact that the differential diagnosis is small, neither was aware of the association with amyloidosis, and
both failed to recognize the cause. This is unfortunate, because early diagnosis would have allowed her to tolerate treatment better.
Abbreviation as in Figure 1.

described, and in whom microvascular coronary ar-
tery dysfunction is common and often severe (15).
On the basis of these basic science observations, a
model of cardiac dysfunction in AL amyloidosis can
be illustrated (Figure 3), in which AL cardiac
amyloidosis can be viewed as a toxic infiltrative
cardiomyopathy, rather than merely an infiltrative
cardiac disease.
Although much emphasis has been placed on
toxicity in AL amyloidosis, recent data suggest a
cardiotoxic effect of the amyloid fibrils themselves.
Fibrils synthesized from light chains
derived from a patient with renal amyloidosis were
found to bind tightly to the surface of human car-
diomyocytes and produced a disturbance of cellular
metabolic activity, but not cell death (16). There are
few animal models of AL amyloidosis, and none
mimic human cardiac amyloidosis of any variety.
Nevertheless, the transgenic mouse model may be
helpful for evaluating therapies, and both a TTR
transgenic mouse and an AL mouse have been
developed that express human mutant TTR and
human light chains, respectively. Ward et al. (17)
developed a transgenic AL mouse model that ex-
presses amyloidogenic lambda-6 light chain variable
domains in the gastrointestinal tract. Using this
model, they demonstrated that doxycycline, fed to
the mice in the drinking water, resulted in a sig-
nificant reduction in amyloid deposition, with a
suggestion, on electron microscopy, that it might not
only prevent fibrillogenesis, but could induce fibril
disruption (17). A similar effect of doxycycline was
seen in a TTR amyloid model (18), and clinical trials of
this drug are in progress (19).
CLINICAL MANIFESTATIONS. Probably the most
common early manifestation of cardiac amyloidosis
of any type is dyspnea on exertion, which progresses
relatively rapidly, and is often followed by periph-
eral edema and ascites. Peripheral edema in AL
amyloidosis may also be due to hypoalbuminemia
originally associated with amyloid-related nephrotic syn-
drome; proteinuria should always be assessed. Dys-
pnea is due to LV diastolic dysfunction. However,
the atria, although they do dilate, are also abnor-
mally stiff, and likely contribute to dyspnea on
exertion. Prominent V waves may be seen in the
pulmonary capillary wedge tracings in the absence of
significant mitral regurgitation. Atrial arrhythmia
may be the initial manifestation of the disease; sur-
prisingly, this is relatively uncommon as a present-
ing feature, particularly in AL amyloidosis. Atrial
infiltration with amyloid deposits results in atrial
dysfunction, and thrombus formation may occur,
even in this setting of sinus rhythm. Thromboem-
bolism may thus be an early manifestation of the
disease, and unless the clinician is aware of the
phenomenon of left atrial systolic dysfunction,
the source of neurological or systemic embolism may
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
F I G U R E 5 Example of Typical Electrocardiograms in AL Amyloidosis
Electrocardiogram showing very low limb lead voltage with indeterminate axis and poor precordial R-wave progression in AL amyloid cardiomyopathy.
Coronary angiography was normal, and the echocardiogram showed a thick left ventricle and no pericardial effusion. This voltage/left ventricular mass
mismatch strongly suggests cardiac amyloidosis. Abbreviation as in Figure 1.
not be recognized. In advanced disease, exertional
syncope, which is most likely due to a low and fixed
cardiac output, can occur, and this has a particularly
poor prognosis (20). Jaw claudication, leg claudica-
tion, and angina may all occur due to small vessel
amyloid deposition (21).
Physical examination of the patient with heart
failure due to cardiac amyloidosis is little different
from that in a patient with other forms of heart fail-
ure. However, there are subtle clues that should raise
the possibility of this diagnosis. In AL amyloidosis,
signs of the noncardiac disease are commonly pre-
sent. Approximately 10% of patients have macro-
glossia, which may vary from obvious tongue
enlargement to subtle tooth indentation of the
tongue (Figure 4). Periorbital bruising in the setting of
heart failure is almost pathognomonic of AL
amyloidosis. Because it may be subtle, the eyelids
should be inspected for small bruises (Figure 4).
Jugular venous pressure frequently reveals an inspi-
ratory rise (Kussmaul sign), a sign that is shared with
patients with constrictive pericarditis. Unlike severe
heart failure caused by most other etiologies, a third
heart sound is uncommon in cardiac amyloidosis, as
is a fourth heart sound. Valvular dysfunction due to
Falk et al. 1329
AL Amyloidosis and the Heart
amyloidosis is rarely severe, although on occasion,
tricuspid regurgitation can be severe. Hepatomegaly
usually reflects congestion, but an enlarged liver may
also be due to amyloid infiltration in patients with AL
amyloidosis. When hepatic infiltration occurs, the
liver is hard and nonpulsatile, and quite distinct from
the congested liver of heart failure. Nephrotic syn-
drome is a common manifestation of AL amyloidosis,
and a clinical clue to the presence of hypo-
albuminemia in a patient with anasarca is extensive
edema in the absence of an elevated jugular venous
pressure. The blood pressure in suspected cardiac
amyloidosis is frequently low, due to a combination
of reduced cardiac output and low peripheral tone. It
should always be measured both supine and stand-
ing, because autonomic nervous system dysfunction
may manifest as significant postural hypotension.
Peripheral neuropathy is also a feature of both AL
amyloidosis and familial TTR amyloidosis. It is sym-
metric, predominantly sensory, and may be missed if
the neurological examination is performed casually.
However, if questioned, patients will often describe
manifestations of early sensory neuropathy in the
lower limbs, such as numbness in the feet or a
sensation of “walking on rolled up socks.” Numbness
1330 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

F I G U R E 6 Typical Echocardiogram in AL Amyloidosis

(Top left and right) End-systolic and end-diastolic frames, respectively, demonstrating normal ejection fraction. Note moderately thick left
ventricular walls with biatrial enlargement. The atrial size changes minimally throughout the cardiac cycle, representing failure of atrial
function, despite sinus rhythm. (Bottom) Septal tissue Doppler recording in the same patient, showing reduction in both systolic and diastolic
longitudinal velocities, despite normal ejection fraction, typical of amyloid cardiomyopathy.

and pain in the hands may be due to carpal tunnel
syndrome, and a history of surgery for carpal tunnel
syndrome may precede the onset of heart failure by
7 or 8 years.
DIAGNOSTIC TESTS
The electrocardiogram (ECG) in AL amyloidosis with
cardiac involvement frequently shows low voltage,
often with an unusual axis, particularly an extreme
right axis (22) (Figure 5). When present, low voltage is
seen in the limb leads, although voltage may be
normal, or occasionally, high, in the precordial leads.
Despite low-voltage QRS complexes, the P-wave is
usually of normal voltage, but frequently abnormal in
morphology, and is often markedly prolonged, rep-
resenting slowed atrial conduction due to amyloid
infiltration. Low-voltage ECG often precedes heart
failure, and may be present before an increase in LV
wall thickness is apparent on an echocardiogram.
This is an early marker of the disease. Low-voltage
QRS complexes are far less common in ATTR than in
AL amyloidosis, despite a greater amyloid burden in
the heart (23).
The echocardiogram typically shows concentric LV
thickening, often with right ventricular thickening
(Figure 6). The LV wall may be more echogenic than in
true LV hypertrophy, and due to the extensive amy-
loid deposits, LV wall thickness frequently equals or
exceeds 15 mm. A wall thickness >18 mm can be seen
in AL amyloidosis, but is more common in ATTR. It is
unusual for hypertensive heart disease to have LV
walls >15 mm, unless hypertension is severe, long-
standing, and persistent; the discrepancy between
increased LV mass on the echocardiogram and low
voltage on the ECG should increase suspicion of car-
diac amyloidosis (23,24). Valves are mildly thickened,
but there is rarely significant valvular regurgitation or
stenosis. If a pacemaker is present, tricuspid regur-
gitation may be more severe, both clinically and
volumetrically, than is usually seen with a pacemaker
lead. This is partly because the amyloid-infiltrated
tricuspid valve may not adequately mold around the
pacemaker wire, and partly because even a volumet-
rically small amount of regurgitation entering a stiff
atrium can further significantly elevate the pressure.
Left atrial contractile dysfunction may be suspected
by the absence of a transmitral A-wave and tissue
JACC VOL. 68, NO. 12, 2016 Falk et al. 1331
SEPTEMBER 20, 2016:1323–41 AL Amyloidosis and the Heart

F I G U R E 7 Typical Impairment of Atrial Function in Cardiac Amyloidosis Despite Sinus Rhythm, Measured by Strain Imaging

(Top left) Absence of atrial expansion during ventricular systole (loss of reservoir function) and absence of atrial contraction during late
ventricular diastole (loss of contractile function). The atrium is acting as a conduit only. (Top right) Normal atrial function in a normal patient.
(Bottom left) A transmitral Doppler pattern corresponding to the atrial strain images. Note the diminutive A-wave, despite normal E-wave
deceleration time, indicating atrial contractile dysfunction.

Doppler a0 in a patient with sinus rhythm (Figure 7).
Although it may be difficult to determine whether a
diminutive transmitral A-wave is a function of true
atrial dysfunction or of restrictive LV pathophysi-
ology, it is likely that there is at least a component of
atrial dysfunction, because cardiac amyloidosis is a
4-chamber disease. Atrial strain imaging often reveals
not only a pattern of impaired atrial shortening dur-
ing the period of atrial systole, but also shows a fail-
ure of the atrium to expand during filling, thereby
acting merely as a conduit throughout
cardiac cycle (Figure 7). Coupled with a low stroke
volume and irregular atrial endocardial surface
because of amyloid deposits, the atrium becomes a
source of thrombus formation, even when in sinus
rhythm.
Doppler and tissue Doppler imaging show diastolic
dysfunction in virtually all patients with cardiac
amyloidosis. It is often severe, with a restrictive
pattern characterized by a short deceleration time on
the transmitral pulsed Doppler and low tissue
Doppler velocities in the LV wall. E/e 0 frequently
exceeds 15, which indicates elevated LV filling
pressure. Speckle strain imaging of the LV shows an
unusual pattern, which strongly suggests cardiac
amyloidosis (25) (Figure 8). The apical longitudinal
strain is near-normal, with marked impairment at the
base, usually with the midventricle falling between
the these extremes. This appearance may be present early
in the disease, and longitudinal contractile dysfunc-
tion may be severe, even when the LV ejection frac-
tion is within the normal range. The stiff ventricle
also causes a prolonged period of diastasis during
measurement of longitudinal contraction, starting in
mid-to-late systole and persisting into mid-diastole.
This contrasts with the normal contractile pattern,
1332 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

F I G U R E 8 Typical Pattern of Color-Coded Speckle Tracking Strain Imaging in a Patient With AL Amyloidosis and a Normal LV Ejection Fraction

(Left panel) Segmental color coding in the apical 4-chamber view, with apex showing darker red, indicating more negative strain compared with pink, lesser
strain at base. (Middle panel) Individual segmental strain for the same view. (Right panel) A bull’s-eye plot derived from the 3 apical views, showing sparing
of apical strain (center of plot) with impaired mid and basal strain. LV ¼ left ventricular; other abbreviation as in Figure 1.

in which the longitudinal ventricular relaxation be-
gins shortly after maximal ventricular shortening.
Pericardial effusion is common, but is rarely large.
Cardiac tamponade is rare, and if it occurs, it may be
difficult to diagnose, because it is often superimposed
on heart failure with an already elevated jugular
venous pressure. In addition, the high right ventric-
ular and right atrial diastolic pressures, and increased
stiffness of the chamber walls can prevent the typical
echocardiographic features of right atrial and right
ventricular diastolic collapse. Thus, tamponade be-
comes a diagnosis of clinical suspicion, and may
only be confirmed if the effusion is tapped under
careful hemodynamic monitoring of cardiac filling
pressure.
Occasionally, patients with cardiac amyloidosis
show an atypical pattern of infiltration, characterized
by asymmetric septal thickening, sometimes with an
LV outflow tract gradient (26). The typical abnor-
mality of preserved apical longitudinal strain may
still be seen in these patients, and the cardiac mag-
netic resonance (CMR) appearance usually suggests
amyloidosis, and not hypertrophic cardiomyopathy.
Cardiac amyloidosis with normal wall thickness has
been described (27). Most of these patients have only
mild cardiac amyloidosis and may have an increased
LV thickness compared with their healthy state, but
it will still be within the normal echocardiographic
range. Rarely, patients have severe heart failure with
a minimal increase in wall thickness; this may be due
to extensive replacement of the myocardium by
amyloid, with a reduction in cellular volume. Such
patients usually have low voltage and a markedly
abnormal CMR. A particularly difficult patient is one
with moderate, unrelated aortic stenosis and cardiac
amyloidosis, usually ATTRwt. Impaired longitudinal
function and decreased LV cavity size can lower car-
diac output, which results in apparent low-flow, low-
gradient aortic stenosis. Severe LV thickening, even
for aortic stenosis patients, may be a clue to the
coexistence of these diseases, and nuclear imaging
with pyrophosphate (PYP) or 2,3-dicarboxypropane-1,
1-diphosphonate (DPD; see the following) can help
determine the presence of cardiac amyloidosis (28).
CMR imaging has emerged as a useful diagnostic
and prognostic tool in several forms of cardiac
amyloidosis. In addition to biventricular thickening
and biatrial enlargement, which can be recognized
easily by echocardiography, there are 2 main CMR
features that suggest the diagnosis of cardiac
amyloidosis (Figure 9): 1) difficulty in nulling the
myocardium following gadolinium injection; and 2) a
noncoronary, usually subendocardial, pattern of
delayed gadolinium enhancement, both within the
ventricular myocardium and in the atrium (29). Gad-
olinium uptake in the atrium is rarely seen in other
JACC VOL. 68, NO. 12, 2016 Falk et al. 1333
SEPTEMBER 20, 2016:1323–41 AL Amyloidosis and the Heart

F I G U R E 9 Use of MR for Diagnosis of Cardiac Amyloidosis and Estimate of Myocardial Amyloid Burden

TI = 100 ms TI = 180 ms TI = 260 ms TI = 920 ms TI = 1455 ms

Bull’s Eye Plot for ECV

0.70
ANT.
1 0.65
7 0.60
6 2 0.55
12 13 8
18 14 0.50

17 15 0.45
11 16 9 0.40
5 3
10 0.35
4 0.30
POST. 0.25

(Top panel) Images from a modified Look-Locker acquisition in a patient with TTR cardiac amyloidosis, shown here in the order of increasing
times after the magnetization inversion (TI). The images were acquired approximately 25 min after injection of 0.2 mmol/kg of gadolinium
contrast, and the T1 in myocardium averaged 490 and 597 ms in the blood pool. The myocardial signal nulls characteristically early compared
with the blood pool signal. (Bottom left panel) A bull’s-eye plot of extracellular volume (ECV) fraction in the same patient, calculated from
pre- and post-contrast relaxation rate measurements for each of 6 myocardial segments in basal, mid, and apical slice locations, respectively.
(Bottom right panel) Images of late gadolinium enhancement (LGE) in a 2-chamber view for the same patient. Although ECV values in this
patient approach the range measured for ECV in myocardial infarcts, the LGE image shows more muted enhancement than is seen for
myocardial infarctions, which reflects the diffuse and global effect of cardiac amyloidosis in comparison to LGE in myocardial infarctions. LGE
may therefore underestimate the severity of disease, whereas ECV provides an objective measure of extracellular space expansion. Other
abbreviations as in Figure 1. Courtesy of Michael Jerosch-Herold, PhD, Brigham and Women’s Hospital, Boston, Massachusetts.

cardiac diseases, is associated with atrial contractile
dysfunction, and is a strong clue to the presence of
cardiac amyloidosis (30). CMR has demonstrated
increased extracellular volume in the hearts of pa-
tients with biopsy-proven amyloidosis, even in the
absence of late gadolinium enhancement (LGE),
which suggests that absence of LGE does not rule out
(usually early) cardiac amyloidosis (31). Although LGE
is not 100% specific for the presence of amyloidosis,
it does have prognostic significance. Among 241 pa-
tients with amyloidosis and 9 asymptomatic carriers,
there was a continuum of LGE in the myocardium,
from none, through subendocardial, to transmural
(32). Extracellular volume (representing amyloid
burden) was measured by T1 mapping. Transmural
LGE was determined to represent advanced cardiac
amyloidosis and predicted death over a mean 2-year
follow-up, with a hazard ratio of 4.1. Importantly,
these investigators pointed out that the evaluation of
LGE was technically far more accurate when phase-
sensitive inversion recovery was used to determine
the null point of the myocardium compared with
magnitude-only inversion recovery, and they recom-
mended that this technique be universally used in the
evaluation of cardiac amyloidosis. T1 mapping alone
has also been evaluated as a prognostic indicator in
cardiac amyloidosis. In a study by the same group
(and probably using some of the same patients), mean
extracellular volume in patients with amyloidosis was
44% compared with 25% in healthy volunteers (31).
Extracellular volume >45% carried a hazard ratio for
death of 3.84 and a pre-contrast T1 of >1,044 ms had a
hazard ratio of 5.39 for mortality. The prognostic
significance of these CMR values remained, even
when more traditional negative prognostic factors
(e.g., elevated N-terminal pro–B-type natriuretic
peptide [NT-proBNP] and grade of diastolic dysfunc-
tion) were evaluated in multivariate analysis.
An attempt was made to determine whether or not
CMR could differentiate AL and TTR amyloidosis (33).
In a group of 97 patients, which consisted of 46 pa-
tients with AL amyloidosis and 51 patients with ATTR,
1334 Falk et al.
AL Amyloidosis and the Heart
F I G U R E 1 0 Multimodality Imaging for Determining Presence and Type of
Cardiac Amyloidosis
(Top left) A planar whole body image of a patient with TTR amyloidosis, showing marked
uptake of 99mtechnetium pyrophosphate (Tc99mPYP) in the heart. Top right, in comparison,
the patient with AL amyloidosis (top right) shows no cardiac isotope uptake, despite a
severe amyloid cardiomyopathy. (Bottom color panel) Single-photon emission computed
tomography Tc99mPYP imaging in TTR (left) and AL amyloidosis (right) confirming intense
uptake in TTR and none in AL amyloidosis. Other abbreviations as in Figure 1.
LV mass was much higher in the ATTR group (228 g)
compared with the AL group (167 g). LGE was more
extensive in the ATTR group, with 90% demon-
strating transmural LGE, compared with 37% of AL
patients. Intriguingly, despite these findings, survival
was significantly better in cardiac ATTR patients.
Although it was concluded that the transmural
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
pattern of LGE helped to distinguish ATTR from AL
amyloidosis, the overlap was considerable, and this
technique should not be used to determine what type
of cardiac amyloidosis is being imaged.
Evaluation of extracellular volume as a percentage
of total LV volume has provided an interesting insight
into the response of the myocardium to amyloid
deposition. It has long been recognized that AL
amyloidosis involving the heart has a worse prognosis
than ATTR, despite a smaller increase in LV mass (9).
Fontana et al. (34) compared 92 patients with AL
amyloidosis with 242 patients with ATTRm and 66
patients with ATTRwt using CMR. As anticipated, LV
mass was much higher in the ATTR group, but this
group also had an 18% increase in the intracellular
space compared with both AL amyloidosis patients
and normal control subjects (34). These data suggest
that there is a true hypertrophic response of the
myocardium to infiltration with amyloid derived from
TTR fibrils, which is not seen with AL amyloidosis.
Intriguingly, and contrary to expectation, the intra-
cellular volume in AL amyloidosis (a marker of car-
diomyocyte volume) did not differ from control
subjects, which implied that the low voltage seen
with AL amyloidosis cannot represent loss of car-
diomyocytes, but must be attributed to some other
mechanism (e.g., myocyte dysfunction).
In the 1980s, there was interest in using
99m
technetium pyrophosphate ( 99m TcPYP) as a
marker for cardiac amyloidosis, because it was found
that this isotope was taken up in the heart of some
patients with cardiac amyloid infiltration (35). How-
ever, this fell into disuse after the sensitivity of the
test was deemed to be low (36). Within the last few
years, it has become apparent that 99m TcPYP and DPD
are avidly taken up by hearts infiltrated by TTR am-
yloid, whereas patients with AL amyloidosis have no,
or minimal, myocardial uptake (37) (Figure 10).
Particularly when single-photon emission computed
tomography analysis is used, a diffuse and intense
myocardial uptake (equal to or greater than rib up-
take) is extremely sensitive and highly specific for
TTR cardiac amyloidosis, to the degree that a strongly
positive DPD or PYP scan in a patient with echocar-
diographic or CMR imaging suggests an infiltrative
cardiomyopathy. The absence of a plasma cell
dyscrasia has been deemed acceptable as specific
enough for the diagnosis of TTR amyloidosis to avoid
a cardiac biopsy (38). Although 99m TcPYP scanning for
AL amyloidosis of the heart is of no value in isolation
(because it is usually negative), the finding of a highly
suggestive echocardiogram or typical CMR appear-
ance of amyloidosis with a strongly positive 99m TcPYP
or DPD scan points away from AL amyloidosis and
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
strongly suggests ATTR. This may be of additional
help in the >20% of patients with ATTR who have an
unrelated monoclonal gammopathy of unknown sig-
nificance (MGUS), because the presence of MGUS in
such patients may lead clinicians to incorrectly as-
sume that they are dealing with AL amyloidosis (39).
As noted previously, circulating free light chains
appear to have an effect on vascular reactivity,
impairing vasodilation. Patients with AL amyloidosis
have, on occasion, typical angina, but normal
epicardial coronary arteries on coronary angiography;
this suggests small vessel dysfunction. Using positron
emission tomography scanning in conjunction with
vasodilator stress, severe impairment in coronary
artery flow was demonstrated in a group of patients
with AL amyloidosis (15). In some patients, treatment
of the amyloidosis resulted in an improvement in
coronary flow, concomitant with the decrease and/or
resolution of angina, which suggests that circulating
free light chains might play a major role in angina in
this subgroup of patients. In centers that are able to
accurately perform this technique, it is useful in
determining the presence or absence of impaired
small cardiac vessel function.
LABORATORY TESTING
Standard laboratory tests in the amyloidoses are
generally unrevealing; however, there may be certain
abnormalities that give a clue to the diagnosis. If
nephrotic syndrome is present, hypoalbuminemia
will be seen, and hypercholesterolemia may be pro-
found. Any sudden elevation of serum cholesterol in
a patient should prompt a search for hypothyroidism
or proteinuria; if the latter is found, and heart failure
is present, the likelihood of a systemic disease is high.
Amyloidosis with heart failure is high on that list.
NT-proBNP is elevated in any cause of heart failure,
but it may be disproportionally high in cardiac
amyloidosis due to the cellular release caused by
direct myocyte compression, in addition to high car-
diac filling pressure.
Troponin levels are frequently chronically elevated
at a low level, and failure to recognize the absence of
the typical rise and fall of troponin occurring with
acute myocardial damage may lead to a misdiagnosis
of myocardial infarction. Amyloid deposits in AL
amyloidosis are due to the misfolding of a part of a
dysfunctional immunoglobulin, and this is reflected
in plasma protein levels. In AL amyloidosis, several
immunoglobulin subclasses are often suppressed.
Unlike multiple myeloma, in which there is usually a
large amount of circulating paraprotein that causes
an abnormal band on serum or urine protein
Falk et al. 1335
AL Amyloidosis and the Heart
electrophoresis, these tests are normal in as many as
one- half of patients with AL amyloidosis, because the
paraprotein level is often low. Immunofixation of
the serum and urine is a much more sensitive test
and usually demonstrates a monoclonal band. Thus,
immunofixation and serum-free light chains should
always be measured when amyloidosis is suspected.
An abnormal free light chain kappa/lambda ratio is
found in >90% of patients with untreated AL
amyloidosis. A normal ratio makes the diagnosis less
likely, but it does not rule it out and certainly does
not exclude other forms of non-AL amyloidosis, in
which the precursor protein is unrelated to a plasma
cell dyscrasia. All patients with suspected AL
amyloidosis should have an initial bone marrow bi-
opsy to determine the percentage of plasma cells and
to rule out both concomitant multiple myeloma
and less common hematologic conditions that may
cause amyloid deposition (e.g., Waldenström macro-
globulinemia and lymphomas). Biomarkers values of
NT-proBNP, troponin T, and free light chains were
shown to be useful in determining prognosis among
newly diagnosed patients with AL amyloidosis,
and the Mayo Clinic developed a staging system
incorporating all 3 of these biomarkers (40). However,
this system is based upon survival after treatment
with older therapeutic regimens and may not be
relevant for patients treated with bortezomib-
containing combination therapies, because survival
appears to be longer than in patients treated with
older therapies (41).
TISSUE BIOPSY
Although the combination of a plasma cell dyscrasia
with an abnormal free light chain ratio and a typical
echocardiographic appearance, with or without CMR
imaging, is highly suggestive of AL cardiac amyloid-
osis, almost 1 in 4 patients with ATTR have associated
MGUS (39), some of whom have an abnormal free
light chain ratio (42). Thus, the sine qua non of
definitive diagnosis in patients with evidence of a
monoclonal gammopathy who are suspected of hav-
ing cardiac AL amyloidosis remains a tissue biopsy
showing amyloid deposits, whether of abdominal fat,
another involved organ, or the heart. At our institu-
tion, we tend to favor endomyocardial biopsy because
it allows for cardiac hemodynamic measurement at
the same time of the biopsy, which can be helpful in
management. However, cardiac biopsy has a small
rate of serious complications and should only be
performed in centers that do this procedure regularly.
Abdominal fat pad biopsy by needle aspiration
has approximately a 70% to 80% sensitivity for
1336 Falk et al. JACC VOL. 68, NO. 12, 2016

AL Amyloidosis and the Heart SEPTEMBER 20, 2016:1323–41

C E NT R A L IL L U ST R A T I O N Diagnosing and Typing Cardiac Amyloidosis in a Patient With Unexplained Heart Failure

Echocardiogram or MRI suggestive of cardiac amyloidosis

Clinical and laboratory evaluation including:

Is plasma-cell dyscrasia present?*

N Y

Myocardial uptake of 99mTcPYP/DPD assessment Bone marrow biopsy +/- cardiac or non-cardiac biopsy

None or trace Strongly positive Immunohistochemistry

Immunohistochemistry shows ambiguous results
strongly positive for
light chains and negative
Is there a transthyretin for transthyretin in Mass spectrometry
protein (TTR) mutation amyloid deposits
present? in amyloid deposits

N Y

Cardiac ATTRwt ATTRm Light -chain

amyloidosis (non-hereditary (hereditary (AL)
is unlikely. form caused form caused amyloidosis
IMPORTANTLY, by wild-type by a genetic
proceed with TTR) mutation of
endomyocardial TTR)
biopsy if clinical
suspicion of
amyloidosis
is still high.

Falk, R.H. et al. J Am Coll Cardiol. 2016;68(12):1323–41.

*The finding of evidence of a plasma cell dyscrasia does not necessarily confirm light-chain (AL) amyloidosis because monoclonal gammopathy of unknown significance
(MGUS) might coexist with transthyretin (TTR) amyloidosis. Thus, if the clinical picture suggests TTR amyloidosis (e.g., isolated cardiac amyloidosis in an elderly man
with a history of carpal tunnel syndrome and no proteinuria or neuropathy), further workup is required to exclude transthyretin amyloidosis (ATTR). A classical
appearance on imaging for amyloidosis, with a strong 99mtechnetium pyrophosphate (Tc99mPYP) (or 2,3-dicarboxypropane-1, 1-diphosphonate [DPD] in Europe) cardiac
uptake, and no evidence of a plasma cell dyscrasia appears to be diagnostic of TTR amyloidosis, without the need for a biopsy (42). ATTRm ¼ mutant transthyretin
amyloidosis; ATTRwt ¼ wild-type transthyretin amyloidosis; MRI ¼ magnetic resonance imaging; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; SPEP ¼ serum
protein electrophoresis.

identifying amyloid deposition, but these figures
come from centers skilled in appropriate staining of
the small amount of tissue often obtained by this
technique. Both false negatives and false positives
(from overstaining) may occur in less experienced
centers (43–45).
Appropriate staining of the biopsy to determine
both the presence and the type of amyloidosis is
critical. Congo red will stain the amyloid pink, with
apple-green birefringence when viewed with polar-
ized microscopy, but several centers, including our
own, prefer sulfated Alcian Blue as an amyloid stain
in cardiac biopsies (46,47). Standard immunohisto-
chemistry and immunofluorescence, even in the most
experienced hands, may give misleading results, and
if the clinical picture is not consistent with the biopsy
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
chemistry, further investigation should be per-
formed. Currently, the gold standard is proteomic
evaluation of amyloid deposits by mass spectrometry.
This technique determines the precise components of
the amyloid deposits, which allows for a highly sen-
sitive and specific result. It is limited to a few centers,
but specimens can be sent there for evaluation, even
if already fixed in a paraffin block. Using this tech-
nique, it has become apparent that immunochemical
staining of tissue amyloid deposits is often an inac-
curate technique (48,49). A flowchart in the Central
Illustration shows an approach to diagnosing cardiac
amyloidosis.
THERAPY. Therapy of AL cardiac amyloidosis is
2-fold: 1) optimal treatment of heart failure, and
2) chemotherapy aimed at abolishing the amyloido-
genic plasma cell dyscrasia. Diuretic agents are
the mainstay of heart failure therapy because
angiotensin-converting enzyme inhibitors and
angiotensin-receptor blockers are poorly tolerated
due to hypotension. We tend to favor a combination
of a loop diuretic agent, usually torsemide, with
spironolactone. Beta-blockers may also aggravate
hypotension and are usually avoided (they may
be used cautiously in selected patients with atrial
fibrillation and a rapid ventricular response).
Although severe diastolic dysfunction is often pre-
sent, there is no role for calcium-channel blockers,
and these drugs often significantly worsen congestive
heart failure. Digoxin appears to offer no benefit in
heart failure due to amyloid cardiomyopathy, and
digoxin toxicity with “therapeutic digoxin levels”
may occur because of altered binding properties (50).
Amyloid infiltration of the atrium results in atrial
arrhythmias in some patients, and there appears to be
a higher incidence of atrial tachycardia and flutter in
relation to the incidence of atrial fibrillation
compared with many other heart diseases. Despite
the poorly functioning atrium in amyloidosis, the
onset of atrial arrhythmias is often associated with
worsening of congestive heart failure, possibly
because of an irregular or excessively fast rhythm.
Attempts at catheter ablation of these arrhythmias
may be difficult due to the multifocal nature, and the
recurrence rate is high (51). If antiarrhythmic agents
are used, those with a negative inotropic or chrono-
tropic effect should be avoided. We have found that
amiodarone is generally quite effective and well-
tolerated, and we have also used dofetilide rela-
tively frequently with good long-term maintenance of
sinus rhythm. Anticoagulation, either with warfarin
or with the oral nonvitamin K antagonist anticoagu-
lants can usually be safely administered to patients
with AL amyloidosis and should be given for any
Falk et al. 1337
AL Amyloidosis and the Heart
atrial arrhythmia. Furthermore, even if the patient is
in sinus rhythm, anticoagulation should be used if the
echocardiogram shows features of left atrial me-
chanical dysfunction, because thrombus formation
and thromboembolism may occur in these patients.
Nonsustained ventricular arrhythmias are uncom-
mon in AL amyloidosis, and sudden death, if it oc-
curs, is most commonly due to sudden profound
bradycardia or pulseless electrical activity (52). It
usually occurs in patients with severe amyloid car-
diomyopathy. There is no proven benefit of either
prophylactic pacing or prophylactic implantable
defibrillator use in these patients, and although small
series report occasional successful defibrillation,
there is little evidence that long-term survival is
affected (53,54). Postural hypotension in AL
amyloidosis may be due to over-diuresis, but is most
commonly related to some degree of autonomic
neuropathy. It may be exposed by diuresis and can be
treated, on occasion, with midodrine. Midodrine-
induced supine hypertension, a complication of
certain autonomic neuropathies, is not seen AL
amyloidosis, and thus high doses of the drug can be
used. An occasional patient may complain of exer-
tional lightheadedness and yet have normal
supine and standing blood pressures. This can be
due to a fixed cardiac output, but it may also be
due to autonomic neuropathy-associated exertional
hypotension. This may be revealed by careful tread-
mill testing and often responds to pre-exercise
midodrine.
Chemotherapy that targets the underlying plasma
cell dyscrasia has changed considerably in the past
decade, with markedly improved response rates and
prolonged survival. It is of critical importance to
involve cardiologists with experience in the disease
during the chemotherapy treatment, and they should
be willing to see patients at frequent intervals
throughout chemotherapy to adjust concomitant
medications. It is beyond the scope of this paper to
address details of specific chemotherapeutic regi-
mens, but the interested reader is directed to an
excellent recent review of this topic (55). Initial
attempts at treating AL amyloidosis with oral
melphalan and prednisone showed a modest survival
benefit among patients without cardiac involvement,
but showed no benefit in AL cardiac amyloidosis (56).
High-dose melphalan chemotherapy with autologous
stem cell transplantation had a significant positive
impact on the percentage of patients who achieved a
complete hematologic remission, and this was
accompanied by an improvement in survival
compared with those who did not achieve remission.
However, this is an aggressive therapy, and patients
1338 Falk et al.
AL Amyloidosis and the Heart
with severe cardiac involvement have a high
treatment-related mortality, even among carefully
selected subjects. It is now less commonly used
as an initial therapy (57). With the institution of
proteosome-inhibiting agents, specifically bortezo-
mib, the prognosis of patients with light chain cardiac
amyloidosis has considerably improved. Bortezomib
is relatively well-tolerated, even in the presence of
amyloid cardiomyopathy, and is usually combined
with dexamethasone and frequently with low-dose
cyclophosphamide (58,59). For example, in patients
without cardiac involvement, 40 mg of dexametha-
sone is usually administered weekly, but this dose
may often worsen heart failure in cardiac amyloid-
osis. In such patients, it is prudent to start with 10 mg
weekly, increasing every week or 2 to the maximum
tolerated dose, while adjusting diuretic agents
accordingly. Concern has been raised about bortezo-
mib cardiotoxicity (60), but this appears to be rare
(61), and the drug is generally well-tolerated in
patients with cardiac amyloidosis. When lenalido-
mide, an immunomodulatory agent, is used in ther-
apy, a paradoxical elevation in B-type natriuretic
peptide or NT-proBNP may be seen, despite evidence
of hematologic improvement; the mechanism for this
is unknown (62,63). High-dose chemotherapy with
autologous stem cell transplantation is generally
reserved for suitable cardiac amyloidosis patients in
whom oral regimens have failed, and may produce a
complete hematologic response. Cardiology input is
important because stem cell collection is often asso-
ciated with fluid retention and hypotension, and
atrial arrhythmias may occur following chemo-
therapy. Generally, hypotension is well-tolerated,
and the temptation to treat with intravenous fluids
should be avoided in the asymptomatic patient.
CARDIAC TRANSPLANTATION
Cardiac transplantation in AL amyloidosis has been
performed, but the outcome depends upon extremely
careful selection of patients. A commitment to pursue
chemotherapy following transplantation for patients
with active hematologic disease is essential, because
systemic disease will otherwise progress, and amy-
loid infiltration of the transplanted heart can occur.
Most patients who have undergone successful
chemotherapy for AL amyloid (defined as normaliza-
tion of their free light chain ratio) have a clinical
improvement in heart failure, and rarely need post-
chemotherapy cardiac transplantation. The patients
in whom cardiac transplantation should be consid-
ered are those with severe cardiac amyloidosis that is
limited to the heart, and in whom systemic
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
chemotherapy is deemed to be too toxic to be toler-
ated because of their heart disease. These patients
have high mortality, and in 1 single-center series,
11 of 31 patients died while awaiting cardiac trans-
plantation. Successful orthotopic heart trans-
plantation occurred in 18 patients, with 1 post-
operative death. Fourteen patients subsequently
underwent high-dose chemotherapy with autologous
stem cell transplantation, with 3 subsequent deaths.
Although the investigators reported no difference in
survival between these patients and age-matched
control subjects in the Scientific Registry of Trans-
plant Recipients database, the numbers were very
small and the death rate on the waiting list was very
high, making precise comparisons difficult.
Data from the Mayo Clinic shed light on the
importance of obtaining a complete hematologic
response to high-dose chemotherapy and autologous
stem cell transplantation after heart transplantation,
as well as on the rarity of the need and/or patient
suitability for cardiac transplantation. Among >3,000
patients with AL amyloidosis seen over a 20-year
period, 23 patients underwent heart transplantation.
Median survival for those able to complete autolo-
gous stem cell transplantation was 6.3 years, and in
the subgroup of 7 patients who achieved a complete
remission, median survival was 10.8 years. Because
one of the main reasons for heart transplantation in
the time period studied was severity of disease pre-
cluding high-dose chemotherapy with autologous
stem cell transplantation (at that time the most
effective therapy for the plasma cell dyscrasia), it is
possible that some of these patients might have
been treatable today with a bortezomib-containing
regimen. This might argue for early heart trans-
plantation evaluation in suitable, severely ill patients
with AL cardiac amyloidosis, while also initiating
chemotherapy and reassessing patients accepted on a
wait list for ongoing transplantation need. This
approach has been adopted by some centers (M.
Semigran, personal communication, March 2016).
Patients with a small LV cavity, such as is seen in
amyloidosis, are not deemed good candidates for a
LV assist device, and right ventricular function is also
often severely impaired in amyloidosis. In a report of
outcomes of LV assist device implantation at the
Mayo Clinic for patients with restrictive cardiomy-
opathy, 10 of 28 patients had amyloid cardiomyopa-
thy, 2 of whom died before hospital discharge. Only 1
patient had AL amyloidosis, but this patient achieved
hematologic remission before device implantation.
One-year overall survival was 64% after LV assist
device implantation, with no difference between
amyloidosis and non-amyloidosis patients, but with
JACC VOL. 68, NO. 12, 2016 Falk et al. 1339
SEPTEMBER 20, 2016:1323–41 AL Amyloidosis and the Heart

poor survival if the LV end-diastolic dimension
was <46 mm.
In addition to chemotherapy to abolish the amy-
loidogenic light chains, several novel adjunctive
therapies have been proposed or are in clinical trials.
In vitro evidence suggests that doxycycline may
prevent the formation of fibrils from light chains and
disrupt fibrils that have already formed, and there is
an ongoing trial of doxycycline in conjunction with
standard chemotherapy.
Antibody therapy has been developed to specif-
ically target misfolded light chain aggregates. A
radiolabeled antibody specifically localized with
human AL amyloid extracts was implanted in mice,
and treatment with this antibody expedited regres-
sion of AL kappa amyloidomas in these animals
(64). Preliminary data from a phase 1/2 study in 27
patients with AL amyloidosis treated with this
antibody showed a decrease in NT-proBNP
following antibody therapy in some AL amyloid-
osis patients with cardiac involvement, but it is
unclear whether this represented ongoing cardiac
improvement related to previous chemotherapy
or an effect of the drug. A phase 3 randomized
multicenter study is currently ongoing, with
patients randomized to chemotherapy alone or
chemotherapy plus antibody.
All amyloid deposits contain an SAP component, a
normal, nonfibrillar plasma glycoprotein that is
believed to render amyloid fibrils resistant to
degradation. In an attempt to rid fibrils of SAP, a
small molecule was developed, (R)-1-[6-[(R)-2-
carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-
2-carboxylic acid (CPHPC), but initial experiments in
humans revealed that the amount of circulating SAP
was too great, and although this drug depleted
circulating SAP (65), it had little effect on amyloid
deposits. This led to the concept of a 2-pronged
approach: depletion of circulating SAP with CPHPC,
followed by the administration of a fully humanized
immunoglobulin-1 anti-SAP monoclonal antibody to
target the SAP on the amyloid fibrils, in the hope that
normal phagocytic processes would resorb the SAP-
depleted fibrils. Using this approach, 16 patients
with amyloidosis, including 8 with AL amyloidosis,
were studied. There was a significant reduction in
amyloid burden noted in most patients over a 6-week
period (66). Of note, none of the 16 patients had car-
diac amyloidosis by trial design, but a trial of this
promising therapy in patients with AL and ATTR
cardiac amyloid is planned to start before the end
of 2016.
SUMMARY
The past decade has seen major advances in diagnosis
and therapy of all forms of amyloidosis, particularly
in AL amyloidosis. Modern diagnostic techniques,
such as CMR and advanced echocardiography, in-
crease the likelihood of diagnosing the disease, but
there is still no substitute for physician awareness of
this condition, without which delayed diagnosis is
inevitable. Early diagnosis is critical for the best
outcome of therapy, and it is hoped that this review
has given the reader insight into the importance of
early diagnosis and of precise amyloid typing, along
with a recognition that a previously hopeless disease
has now rapidly become a treatable and possibly
curable condition.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Rodney H. Falk, Division of Cardiology Brigham and
Women’s Hospital, 75 Francis Street, Boston, Massa-
chusetts 02115. E-mail: rfalk@partners.org.

REFERENCES

1. Brahmanandam V, McGraw S, Mirza O, et al.
Regression of cardiac amyloidosis after stem cell
transplantation assessed by cardiovascular magnetic
resonance imaging. Circulation 2014;129:2326–8.
2. Hawkins PN. Serum amyloid P component
scintigraphy for diagnosis and monitoring
amyloidosis. Curr Opin Nephrol Hypertens 2002;
11:649–55.
3. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis,
prognosis, and therapy of transthyretin amyloid-
osis. J Am Coll Cardiol 2015;66:2451–66.
4. Palumbo A, Anderson K. Multiple myeloma.
N Engl J Med 2011;364:1046–60.
5. Hasserjian RP, Goodman HJ, Lachmann HJ,
et al. Bone marrow findings correlate with clinical
outcome in systemic AL amyloidosis patients.
Histopathology 2007;50:567–73.
6. Kyle RA, Linos A, Beard CM, et al. Incidence and
natural history of primary systemic amyloidosis in
Olmsted County, Minnesota, 1950 through 1989.
Blood 1992;79:1817–22.
7. Comenzo RL. Out, out–making amyloid’s candle
briefer. N Engl J Med 2015;373:1167–9.
8. Larsen BT, Mereuta OM, Dasari S, et al. Corre-
lation of histomorphological pattern of cardiac
amyloid deposition with amyloid type: a histo-
logical and proteomic analysis of 108 cases. His-
topathology 2016;68:648–56.
9. Dubrey SW, Cha K, Skinner M, et al. Familial
and primary (AL) cardiac amyloidosis:
echocardiographically similar diseases with
distinctly different clinical outcomes. Heart 1997;
78:74–82.
10. Dubrey S, Mendes L, Skinner M, et al. Reso-
lution of heart failure in patients with AL
amyloidosis. Ann Intern Med 1996;125:481–4.
11. Liao R, Jain M, Teller P, et al. Infusion of light
chains from patients with cardiac amyloidosis
causes diastolic dysfunction in isolated mouse
hearts. Circulation 2001;104:1594–7.
12. Brenner DA, Jain M, Pimentel DR, et al. Human
amyloidogenic light chains directly impair car-
diomyocyte function through an increase in
cellular oxidant stress. Circ Res 2004;94:
1008–10.
1340 Falk et al.
AL Amyloidosis and the Heart
13. Mishra S, Guan J, Plovie E, et al. Human amy-
loidogenic light chain proteins result in cardiac
dysfunction, cell death, and early mortality in
zebrafish. Am J Physiol Heart Circ Physiol 2013;
305:H95–103.
14. Migrino RQ, Truran S, Gutterman DD, et al.
Human microvascular dysfunction and apoptotic
injury induced by AL amyloidosis light chain pro-
teins. Am J Physiol Heart Circ Physiol 2011;301:
H2305–12.
15. Dorbala S, Vangala D, Bruyere J Jr., et al.
Coronary microvascular dysfunction is related to
abnormalities in myocardial structure and function
in cardiac amyloidosis. J Am Coll Cardiol HF 2014;
2:358–67.
16. McWilliams-Koeppen HP, Foster JS,
Hackenbrack N, et al. Light chain amyloid fibrils
cause metabolic dysfunction in human car-
diomyocytes. PLoS One 2015;10:e0137716.
17. Ward JE, Ren R, Toraldo G, et al. Doxycycline
reduces fibril formation in a transgenic mouse
model of AL amyloidosis. Blood 2011;118:6610–7.
18. Cardoso I, Martins D, Ribeiro T, et al. Synergy
of combined doxycycline/TUDCA treatment in
lowering transthyretin deposition and associated
biomarkers: studies in FAP mouse models. J Transl
Med 2010;8:74.
19. Obici L, Cortese A, Lozza A, et al. Doxycycline
plus tauroursodeoxycholic acid for transthyretin
amyloidosis: a phase II study. Amyloid 2012;19
Suppl 1:34–6.
20. Chamarthi B, Dubrey SW, Cha K, et al. Features
and prognosis of exertional syncope in light-chain
associated AL cardiac amyloidosis. Am J Cardiol
1997;80:1242–5.
21. Ing EB, Woolf IZ, Younge BR, et al. Systemic
amyloidosis with temporal artery involvement
mimicking temporal arteritis. Ophthalmic Surg
Lasers 1997;28:328–31.
22. Mussinelli R, Salinaro F, Alogna A, et al.
Diagnostic and prognostic value of low QRS volt-
ages in cardiac AL amyloidosis. Ann Noninvasive
Electrocardiol 2013;18:271–80.
23. Rapezzi C, Merlini G, Quarta CC, et al. Systemic
cardiac amyloidoses: disease profiles and clinical
courses of the 3 main types. Circulation 2009;120:
1203–12.
24. Carroll JD, Gaasch WH, McAdam KP. Amyloid
cardiomyopathy: characterization by a distinctive
voltage/mass relation. Am J Cardiol 1982;49:9–13.
25. Phelan D, Collier P, Thavendiranathan P, et al.
Relative apical sparing of longitudinal strain using
two-dimensional speckle-tracking echocardiogra-
phy is both sensitive and specific for the diagnosis
of cardiac amyloidosis. Heart 2012;98:1442–8.
26. Philippakis AA, Falk RH. Cardiac amyloidosis
mimicking hypertrophic cardiomyopathy with
obstruction: treatment with disopyramide. Circu-
lation 2012;125:1821–4.
27. Lee GY, Kim K, Choi JO, et al. Cardiac
amyloidosis without increased left ventricular wall
thickness. Mayo Clin Proc 2014;89:781–9.
28. Longhi S, Lorenzini M, Gagliardi C, et al.
Coexistence of degenerative aortic stenosis and
wild-type transthyretin-related cardiac amyloid-
osis. J Am Coll Cardiol Img 2016;9:325–7.
29. Fontana M, Chung R, Hawkins PN, et al. Car-
diovascular magnetic resonance for amyloidosis.
Heart Fail Rev 2015;20:133–44.
30. Kwong RY, Heydari B, Abbasi S, et al. Char-
acterization of cardiac amyloidosis by atrial late
gadolinium enhancement using contrast-enhanced
cardiac magnetic resonance imaging and correla-
tion with left atrial conduit and contractile func-
tion. Am J Cardiol 2015;116:622–9.
31. Banypersad SM, Fontana M, Maestrini V, et al.
T1 mapping and survival in systemic light-chain
amyloidosis. Eur Heart J 2015;36:244–51.
32. Fontana M, Pica S, Reant P, et al. Prognostic
value of late gadolinium enhancement cardiovas-
cular magnetic resonance in cardiac amyloidosis.
Circulation 2015;132:1570–9.
33. Dungu JN, Valencia O, Pinney JH, et al. CMR-
based differentiation of AL and ATTR cardiac
amyloidosis. J Am Coll Cardiol Img 2014;7:133–42.
34. Fontana M, Banypersad SM, Treibel TA, et al.
Differential myocyte responses in patients with
cardiac transthyretin amyloidosis and light-chain
amyloidosis: a cardiac MR imaging study. Radi-
ology 2015;277:388–97.
35. Falk RH, Lee VW, Rubinow A, et al. Sensitivity
of technetium-99m-pyrophosphate scintigraphy
in diagnosing cardiac amyloidosis. Am J Cardiol
1983;51:826–30.
36. Gertz MA, Brown ML, Hauser MF, et al. Utility
of technetium Tc 99m pyrophosphate bone scan-
ning in cardiac amyloidosis. Arch Intern Med 1987;
147:1039–44.
37. Rapezzi C, Quarta CC, Guidalotti PL, et al.
Usefulness and limitations of 99mTc-3,3-
diphosphono-1,2-propanodicarboxylic acid scintig-
raphy in the aetiological diagnosis of amyloidotic
cardiomyopathy. Eur J Nucl Med Mol Imaging 2011;
38:470–8.
38. Gillmore JD, Maurer MS, Falk RH, et al.
Non-biopsy diagnosis of cardiac transthyretin
amyloidosis. Circulation 2016;133:2404–12.
39. Pinney JH, Whelan CJ, Petrie A, et al. Senile
systemic amyloidosis: clinical features at presen-
tation and outcome. J Am Heart Assoc 2013;2:
e000098.
40. Kumar S, Dispenzieri A, Lacy MQ, et al.
Revised prognostic staging system for light chain
amyloidosis incorporating cardiac biomarkers and
serum free light chain measurements. J Clin Oncol
2012;30:989–95.
41. Sperry BW, Ikram A, Hachamovitch R, et al.
Efficacy of chemotherapy for light-chain
amyloidosis in patients presenting with symp-
tomatic heart failure. J Am Coll Cardiol 2016;67:
2941–8.
42. Maleszewski JJ, Murray DL, Dispenzieri A,
et al. Relationship between monoclonal gamm-
opathy and cardiac amyloid type. Cardiovasc
Pathol 2013;22:189–94.
43. Vrana JA, Theis JD, Dasari S, et al. Clinical
diagnosis and typing of systemic amyloidosis in
subcutaneous fat aspirates by mass spectrometry-
based proteomics. Haematologica 2014;99:
1239–47.
44. Gertz MA, Li CY, Shirahama T, et al. Utility of
subcutaneous fat aspiration for the diagnosis of
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
systemic amyloidosis (immunoglobulin light
chain). Arch Intern Med 1988;148:929–33.
45. Libbey CA, Skinner M, Cohen AS. Use of
abdominal fat tissue aspirate in the diagnosis of
systemic amyloidosis. Arch Intern Med 1983;143:
1549–52.
46. Maleszewski JJ. Cardiac amyloidosis: pathol-
ogy, nomenclature, and typing. Cardiovasc Pathol
2015;24:343–50.
47. Pomerance A, Slavin G, McWatt J. Experience
with the sodium sulphate-Alcian Blue stain for
amyloid in cardiac pathology. J Clin Pathol 1976;
29:22–6.
48. Sethi S, Vrana JA, Theis JD, et al. Laser
microdissection and mass spectrometry-based
proteomics aids the diagnosis and typing of renal
amyloidosis. Kidney Int 2012;82:226–34.
49. Theis JD, Dasari S, Vrana JA, et al. Shotgun-
proteomics-based clinical testing for diagnosis and
classification of amyloidosis. J Mass Spectrom
2013;48:1067–77.
50. Rubinow A, Skinner M, Cohen AS. Digoxin
sensitivity in amyloid cardiomyopathy. Circulation
1981;63:1285–8.
51. Barbhaiya CR, Kumar S, Baldinger SH, et al.
Electrophysiologic assessment of conduction ab-
normalities and atrial arrhythmias associated with
amyloid cardiomyopathy. Heart Rhythm 2016;13:
383–90.
52. Sayed RH, Rogers D, Khan F, et al. A study of
implanted cardiac rhythm recorders in advanced
cardiac AL amyloidosis. Eur Heart J 2015;36:
1098–105.
53. Kristen AV, Dengler TJ, Hegenbart U, et al.
Prophylactic implantation of cardioverter-
defibrillator in patients with severe cardiac
amyloidosis and high risk for sudden cardiac
death. Heart Rhythm 2008;5:235–40.
54. Varr BC, Zarafshar S, Coakley T, et al.
Implantable cardioverter-defibrillator placement
in patients with cardiac amyloidosis. Heart Rhythm
2014;11:158–62.
55. Kastritis E, Dimopoulos MA. Recent advances
in the management of AL amyloidosis. Br J
Haematol 2016;172:170–86.
56. Skinner M, Anderson J, Simms R, et al. Treat-
ment of 100 patients with primary amyloidosis: a
randomized trial of melphalan, prednisone, and
colchicine versus colchicine only. Am J Med 1996;
100:290–8.
57. Merlini G, Palladini G. Amyloidosis: is a cure
possible? Ann Oncol 2008;19 Suppl 4:iv63–6.
58. Jimenez-Zepeda VH, Duggan P, Neri P, et al.
Bortezomib-containing regimens for the treatment
of newly diagnosed and relapsed amyloid light
chain amyloidosis: a single-center experience. Clin
Lymphoma Myeloma Leuk 2016;16:e79–84.
59. Palladini G, Sachchithanantham S, Milani P,
et al. A European collaborative study of cyclo-
phosphamide, bortezomib, and dexamethasone in
upfront treatment of systemic AL amyloidosis.
Blood 2015;126:612–5.
60. Enrico O, Gabriele B, Nadia C, et al. Unex-
pected cardiotoxicity in haematological
JACC VOL. 68, NO. 12, 2016
SEPTEMBER 20, 2016:1323–41
bortezomib treated patients. Br J Haematol 2007;
138:396–7.
61. Xiao Y, Yin J, Wei J, et al. Incidence and
risk of cardiotoxicity associated with bortezo-
mib in the treatment of cancer: a systematic
review and meta-analysis. PLoS One 2014;9:
e87671.
62. Dispenzieri A, Dingli D, Kumar SK, et al.
Discordance between serum cardiac biomarker and
immunoglobulin-free light-chain response in
patients with immunoglobulin light-chain amy-
loidosis treated with immune modulatory drugs.
Am J Hematol 2010;85:757–9.
63. Tapan U, Seldin DC, Finn KT, et al. Increases in
B-type natriuretic peptide (BNP) during treatment
with lenalidomide in AL amyloidosis. Blood 2010;
116:5071–2.
64. Wall JS, Kennel SJ, Williams A, et al. AL am-
yloid imaging and therapy with a monoclonal
antibody to a cryptic epitope on amyloid fibrils.
PLoS One 2012;7:e52686.
65. Gillmore JD, Tennent GA, Hutchinson WL,
et al. Sustained pharmacological depletion of
serum amyloid P component in patients with sys-
temic amyloidosis. Br J Haematol 2010;148:
760–7.
Falk et al. 1341
AL Amyloidosis and the Heart
66. Richards DB, Cookson LM, Berges AC, et al.
Therapeutic clearance of amyloid by antibodies to
serum amyloid P component. N Engl J Med 2015;
373:1106–14.
KEY WORDS cardiomyopathy, multiple
myeloma, TTR amyloidosis
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