JACC: HEART FAILURE VOL. 8, NO.

9, 2020

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION

MINI-FOCUS ISSUE: CARDIAC AMYLOIDOSIS

STATE-OF-THE-ART REVIEW

Utility of Biomarkers in Cardiac Amyloidosis

Arianna Pregenzer-Wenzler, MD,a Jo Abraham, MD,a Kelsey Barrell, MD,a Tibor Kovacsovics, MD,b
Jose Nativi-Nicolau, MDa

HIGHLIGHTS

Biomarkers can be used for patients with light chain amyloidosis and transthyretin
amyloidosis for staging and prognosis.

Biomarkers can be used for patients with light chain amyloidosis to determine disease
progression and response to therapies.

The role of biomarkers to determine disease progression and response to therapies in
patient with transthyretin amyloidosis is an active area of investigation.

ABSTRACT

Cardiac amyloidosis is a growing field, with advancements in diagnosis and management. Cardiac biomarkers are used
to predict survival and to develop severity staging systems. Cardiac biomarkers are also used in clinical practice to stratify
patients for treatment and to evaluate response to therapies. The current review summarizes the major clinical utility of
current biomarkers in patients with cardiac amyloidosis and provides insights about future areas of investigation.
(J Am Coll Cardiol HF 2020;8:701–11) Published by Elsevier on behalf of the American College of Cardiology Foundation.

A myloidosis refers to a group of systemic

diseases caused by the extracellular accumu-
lation of insoluble, misfolded protein aggre-
gates in various organs (Figure 1) (1). The types of
The purpose of this review was to summarize the
history and current clinical use of cardiac biomarkers
for assessment of prognosis and response to therapy
in cardiac amyloidosis (Central Illustration) and to
amyloidosis that are commonly associated with car- describe the ongoing areas of investigation into car-
diac involvement are acquired monoclonal immuno- diac amyloidosis.
globin light chain amyloidosis (AL), wild-type
transthyretin amyloidosis (ATTRwt), and hereditary CARDIAC BIOMARKERS FOR STAGING
transthyretin amyloidosis (ATTRm) (2). Regardless AND PROGNOSIS
of cause, the degree of cardiac involvement at the
time of diagnosis is the most important prognostic STAGING OF AL. The prognosis of patients with AL is
indicator. highly dependent on the extent of cardiac

From the aCardiac Amyloidosis Program, University of Utah School of Medicine, Salt Lake City, Utah; and the bHuntsman Cancer
Institute, Salt Lake City, Utah. Dr. Nativi-Nicolau’s institution has received funding for clinical trials from Pfizer, Akcea and Eidos;
and educational grants from Pfizer; and he is a consultant for Pfizer, Eidos, Akcea, and Alnylam. Dr. Kovacsovics has received
research support from Prothena and Janssen. All other authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the JACC: Heart Failure author instructions page.

Manuscript received November 18, 2019; revised manuscript received February 20, 2020, accepted March 5, 2020.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2020.03.007

702 Pregenzer-Wenzler et al.
Biomarkers in Amyloidosis
ABBREVIATIONS
AND ACRONYMS
ADAMTS-13 =
metalloproteinase with
thrombospondin type-1
repeats 13
AL = light chain amyloidosis
ATTR = transthyretin
amyloidosis
ATTRm = mutant transthyretin
amyloidosis
ATTRwt = wild-type
transthyretin amyloidosis
BNP = B-type natriuretic
peptide
CA = cardiac amyloidosis
cTn = cardiac troponin
cTnI = cardiac troponin I
cTnT = cardiac troponin T
ECM = extra cellular matrix
eGFR = estimated glomerular
filtration rate
Gal-3 = galactin-3
GDF = growth differentiation
factor
HFrEF = heart failure with
reduced ejection fraction
HGF = hepatocyte growth
factor
hs-cTn = high-sensitivity
cardiac troponin
MMPs = matrix
metalloproteinases
MR-proADM = mid-regional
pro-adrenomedullin
MR-proANP = midregional
pro-atrial natriuretic peptide
NT-proBNP = N-terminal pro–
B-type natriuretic peptide
NYHA = New York Heart
Association
OPG = osteoprotegerin
OPN = osteopontin
PBSCT = peripheral blood stem
cell transplant
sST2 = soluble suppression of
tumorigenicity 2
TIMPs = tissue inhibitors of
metalloproteinases
TUDCA = tauroursodeoxycholic
acid
UDCA = ursodeoxycholic acid
VWF = von Willebrand factor
involvement at the time of diagnosis. Given
that cardiac troponins T (cTnT) and I (cTnI)
have been shown to be both sensitive and
specific markers of cardiac injury (3), Dis-
pernzieri et al. (4) reported that patients with
detectable cTnT or cTnI at diagnosis of AL
had a median observed survival (OS) of 6 to
8 months compared to a median OS of
approximately 21 months in patients with
undetectable troponin levels. At the same
time, Palladini et al. (5) analyzed the
expression of N-terminal pro–B-type natri-
uretic peptide (NT-proBNP) in patients newly
diagnosed with AL and found a correlation
between elevated NT-proBNP levels and
both clinical cardiac involvement and
decreased OS.
A staging system for AL amyloidosis was
developed in 2004 by using patients with
newly diagnosed AL seen at the Mayo Clinic
between 1979 and 2000. This system, later
termed the MAYO2004 staging system,
defined patients as Stages I to III based on
the absence of elevated cardiac biomarker
(Stage I) versus the presence of a single
elevated cardiac biomarker, cTnT/cTnI or
NT-proBNP (Stage II) versus the elevation of
both cardiac biomarkers (Stage III), with a
median OS of approximately 27, 11, and
4 months, respectively (p < 0.0001) (6). For
this staging system, the threshold values of
cardiac biomarkers were set at the lower
limit of detection for cTnT at <0.035 mg/l,
detection of cTnI at <0.1 m g/l, and at the
upper limit of normal for NT-proBNP
at <332 ng/l (Table 1) (6). The MAYO2004
staging system was revised and expanded in
2012 (MAYO2012) to include a third inde-
pendent prognostic indicator of OS, the
clonal free light chain burden difference
of $18 mg/dl. This allowed for Stages I to IV
with a median OS of approximately 94, 40,
14, and 6 months, respectively (p < 0.001)
(Figure 2A) (7). In the MAYO2012 staging
system, the cutoff value for NT-proBNP was
1,800 pg/ml, and the cutoff for cTnT
was $0.025 ng/ml (Table 1) (7). The
MAYO2012 system can also be calculated
using high-sensitivity cTnT, however a cut-
off of 40 pg/ml is recommended (8).
A few studies have gone on to analyze the
prognostic value of the Mayo staging system
in patients undergoing treatment for AL.
JACC: HEART FAILURE VOL. 8, NO. 9, 2020
SEPTEMBER 2020:701–11
Wechalekar et al. (9) evaluated the outcomes in
response to chemotherapy in a large cohort of pa-
tients classified as Stage III by the original Mayo
staging system. The investigators’ results, published
in 2013, demonstrated a median OS of 7.1 months and
identified an ultra-high risk population (MAYO3b)
characterized by NT-proBNP concentrations of
>8,500 ng/l and troponin-T >0.035 m g/l (Table 1), with
an OS of only 5 months (Figure 2B) (9).
The staging systems in AL amyloidosis have been
accepted for prognosis in clinical practice; however,
further research is required in specific populations,
such as patients with atrial fibrillation, who are
known to have elevated natriuretic peptides. Also,
the natriuretic peptides are cleared by the kidneys,
and their levels are affected by the glomerular filtra-
tion rate. Palladini et al. (10) demonstrated that, in
patients with AL amyloidosis with an estimated
glomerular filtration rate (eGFR) of <15 ml/
min/1.73 m 2, NT-proBNP loses its prognostic value,
whereas the B-type natriuretic peptide still predicts
survival. A study in 1,224 patients by Dittirch et al. (11)
from the Heidelberg Center, compared the perfor-
mance of all AL staging systems in patients with atrial
fibrillation and in patients with an eGFR <50. They
found that MAYO2004, MAYO2012, and MAYO3b
performance remained significant in patients with
eGFR <50. However, the performance of all of them is
reduced in patients with atrial fibrillation but less
affected in patients assessed using the MAYO3b sys-
tem. These findings favor the MAYO3b system in pa-
tients with eGFR <50 and in patients with atrial
fibrillation.
STAGING OF ATTR. In 2016, Grogan et al. (12) re-
ported a retrospective review of patients with
ATTRwt between 1965 and 2013 to explore cTnT and
NT-proBNP as predictors of survival. Based on their
findings, a staging system was proposed that uses the
same Stages I to III, defined in the Mayo staging sys-
tem for AL, based on the presence or absence of
elevation in cTnT and/or NT-proBNP. The ATTRwt
staging system uses a cutoff point for cTnT
of $0.05 ng/ml; however, the cutoff value for NT-
proBNP determined to be prognostic in ATTRwt was
significantly higher, at 3,000 pg/ml, than the cutoff
point of 1,800 pg/ml used by the revised Mayo staging
system for AL (Table 2). The present study found a
median OS of 66, 40, and 20 months for Stages I, II,
and III, respectively (Figure 2C) (12).
Until very recently, no formal staging system had
been proposed for ATTRm cardiac amyloidosis. In
2017, Gillmore et al. (13) proposed a staging system
based on NT-proBNP and eGFR that used
JACC: HEART FAILURE VOL. 8, NO. 9, 2020 Pregenzer-Wenzler et al. 703
SEPTEMBER 2020:701–11 Biomarkers in Amyloidosis

F I G U R E 1 Amyloidosis Fibril Deposition

A precursor protein misfold and an aggregate into amyloid fibrils. Amyloidosis fibrils deposit in the extracellular space of several organs. In the myocardium, it causes
predominantly diastolic heart failure with release of biomarkers. BNP ¼ brain natriuretic peptide; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide. Adapted
with permission from Nativi-Nicolau (30).

retrospective analysis of a mixed population of pa-
tients with ATTR cardiac amyloidosis identified as
having ATTRwt, p.Val142Ile (V122I) ATTRm or other
ATTRm (13). Similar to the staging system proposed
by Grogan et al. (12), the study by Gillmore found that
the optimal cutoff point for NT-proBNP was 3,000 pg/
ml and 45 ml/min/1.73 m 2 for eGFR. It defines Stages I
(NT-proBNP and eGFR less than or equal to the cutoff
point) to III (both NT-proBNP and eGFR above the
cutoff point) (Table 2), with OS of the combined
cohort for Stages I, II, and III as approximately 62, 47,
and 24 months, respectively (Figure 2D). Although
this staging system is presented as being applicable to
both ATTRwt and ATTRm, it was noted that on

C ENTR AL I LL U STRA T I O N Utility of Biomarkers in Cardiac Amyloidosis

Biomarkers for Staging & Prognosis

Light Chain Amyloidosis Wild-Type ATTR Amyloidosis Mutant ATTR Amyloidosis
- NT-proBNP - NT-proBNP - NT-proBNP
- cTnT/cTnl - cTnT/cTnl - eGFR
- Free light chain difference

Biomarkers for Response to Therapies

Light Chain Amyloidosis
- NT-proBNP
- cTnT/cTnl
- Serum free light chains
Cardiac Amyloidosis
Wild-Type & Mutant ATTR Amyloidosis
- NT-proBNP
- cTnT/cTnl
- Serum transthyretin levels (pre-albumin)

Pregenzer-Wenzler, A. et al. J Am Coll Cardiol HF. 2020;8(9):701–11.

Cardiac biomarkers can be used to estimate staging and prognosis and also to assess response to therapies and disease progression.
ATTR ¼ transthyretin amyloidosis; cTnT/cTnI ¼ cardiac troponin T/cardiac troponin I; eGFR ¼ estimated glomerular filtration rate;
NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide.
704 Pregenzer-Wenzler et al. JACC: HEART FAILURE VOL. 8, NO. 9, 2020

Biomarkers in Amyloidosis SEPTEMBER 2020:701–11

T A B L E 1 Biomarkers for Staging and Prognosis in Light Chain Amyloidosis

First Author (Year) (Ref. #) Prognosis

(Staging System) Type Biomarkers Cutoff Values Staging Median OS

Dispenzieri et al. 2004 (6) AL NT-proBNP <332 ng/l Stage I ¼ NT-proBNP and cTn below Stage I ¼ 27 m
(MAYO2004) cTnT <0.035 mg/l Stage II ¼ NT-proBNP and cTn only 1 above Stage II ¼ 11 m
cTnI <0.1 mg/l Stage III ¼ NT-proBNP and cTn above Stage III ¼ 4 m
Kumar et al. 2012 (7) AL cTnT $0.025 ng/ml Stage I ¼ all below cutoff Stage I ¼ 94 m
(MAYO2012) NT-proBNP $1,800 pg/ml Stage II ¼ 1 above Stage II ¼ 40 m
FLC-diff $18 mg/dl
Stage III ¼ 2 above Stage III¼ 14 m
Stage IV ¼ 3 above Stage IV ¼ 6 m
Wechalekar et al. 2013 (9) AL NT-proBNP >8,500 ng/l Stage IIIb ¼ NT-proBNP >8,500 ng/l Stage IIIb ¼ 5 m
(MAYO3b)

AL ¼ light chain amyloidosis; cTn ¼ cardiac troponin; FLC-diff ¼ free light chain difference; m ¼ months; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide;
OS ¼ observed survival.

F I G U R E 2 Survival of Patients With Amyloidosis Based on Staging

(A) Survival in patients with light chain amyloidosis using the MAYO2010 staging system. Adapted with permission from Kumar et al. (7). (B) Survival in patient with
light chain amyloidosis using the MAYO3b staging system. Reproduced with permission from Wechalekar et al. (9). (C) Survival in patients with wild-type transthyretin
amyloidosis (ATTR) amyloidosis. Reproduced with permission from Grogan et al. (4). (D) Survival in patients with mutant ATTR amyloidosis. Reproduced with permission
from Gillmore et al. (13).
JACC: HEART FAILURE VOL. 8, NO. 9, 2020 Pregenzer-Wenzler et al. 705
SEPTEMBER 2020:701–11 Biomarkers in Amyloidosis

T A B L E 2 Biomarkers for Staging and Prognosis in ATTR Amyloidosis

Prognosis
First Author, Year (Ref. #) Type Biomarkers Cutoff Values Staging Median OS

Grogan et al., 2016 (12) ATTRwt cTnT $0.05 ng/ml Stage I ¼ all below cutoff Stage I ¼ 66 m
NT-proBNP $ 3,000 pg/ml Stage II ¼ 1 above Stage II ¼ 40 m
Stage III ¼ 2 above Stage III ¼ 20 m
Gillmore et al., 2017 (13) ATTRwt, NT-proBNP $ 3,000 ng/l Stage I ¼ NT-proBNP #3,000 ng/l and Stage I ¼ 69 m
ATTRm eGFR # 45 ml/min eGFR $45 ml/min
Stage II ¼ all other combinations Stage II ¼ 47 m
Stage III ¼ NT-proBNP >3,000 ng/l and Stage III ¼ 24 m
eGFR <45 ml/min

ATTRwt ¼ wild-type transthyretin amyloidosis; ATTRm ¼ mutant transthyretin amyloidosis; eGFR ¼ estimated glomerular filtration rate; other abbreviations as in Table 1.

subgroup analysis, the V122I mutation seems to be
associated with a shorter OS in all 3 stages; however,
this mutation is predominant in some ethnic groups,
and the shorter survival could result from multiple
factors besides genotype (13).
Serum transthyretin (TTR), also known as pre-
albumin, is another biomarker that has been evalu-
ated for prognosis. In a recent study by Hanson et al.
(14), patients with ATTRwt with low serum levels of
TTR <18 mg/dl (normal range, 18 to 45 mg/dl) had a
median survival of 2.8 years, compared to 4.1 years in
patients with serum TTR levels above the cutoff.
There are some considerations for the interpreta-
tion of cardiac troponins. Biomarker cTnI has several
manufacturers and essays that are not harmonized,
and the results are not comparable among the essays.
In contrast, cTnT essays are developed from only 1
manufacturer and have good standardization, making
results comparable among them. High-sensitivity
troponin essays were introduced for earlier detec-
tion of myocardial injury; however, they require
specific cutoff values based on sex, and healthy in-
dividuals can have small undetectable levels (15).
CARDIAC BIOMARKERS FOR ASSESSMENT OF
RESPONSE TO THERAPY
response to treatment. The first of these studies, a
prospective study published in 2006, demonstrated
both clinical improvement in heart failure symptoms
and prolonged median OS in patients who achieved
both an NT-proBNP and a hematologic response
following 3 cycles of chemotherapy, whereas patients
who had progression of NT-proBNP levels did not
receive clinical or survival benefits, despite a
demonstrated hematologic response (18). These
findings were confirmed in larger, retrospective
studies published in 2010. One of those studies
examined specifically NT-proBNP levels at 6 months
in response to various treatment regimens (19), and
another study aimed specifically at evaluating the
efficacy of bortezomib in treatment of AL (20). Later,
in response to the need for updated criteria to assess
hematologic and cardiac response to the treatment of
AL, a consensus paper described updated criteria to
assess hematologic and cardiac response to treatment
of AL amyloidosis (21). The criteria were based on
data from European and U.S. centers and validated in
the cohort studied by Palladini et al. (10). That study
demonstrated that a 30% reduction in the NT-proBNP
levels in response to treatment is the best indicator of
cardiac response and strongly correlated to increase
median OS. In addition, that report showed that

ASSESSMENT OF THERAPEUTIC RESPONSE IN

AL. The potential utility of NT-proBNP as a tool to
assess response to therapy for patients with AL was
alluded to in the first study by Palladini et al. (5),
which showed that most patients with elevated
NT-proBNP levels at diagnosis who achieved hema-
tologic response to treatment also demonstrated a
significant reduction in their NT-proBNP levels. Since
that time, several studies of patients receiving treat-
ment for AL have demonstrated
correlation between a defined decrease in NT-proBNP
(NT-proBNP response) (16) and increased overall
survival in response to therapy (17), confirming the
utility of cardiac biomarkers in the assessment of
T A B L E 3 Biomarkers for Therapeutic Response in AL Amyloidosis
Heart response
1. NT-proBNP response (>30% and >300 ng/l decrease in patients with baseline
NT-proBNP $650 ng/l) or
2. NYHA functional class response ($2 class decrease in subjects with baseline NYHA functional
class III or IV)
Heart progression
1. NT-proBNP progression (>30% and >300 ng/l increase*) or
2. cTn progression ($33% increase), or
a significant 3. Ejection fraction progression ($10% decrease)
Adapted with permission from Comenzo et al. (16). *Patients with progressively worsening renal function were
not scored for NT-proBNP progression.
NYHA ¼ New York Heart Association; other abbreviations as in Tables 1 and 2.
706 Pregenzer-Wenzler et al. JACC: HEART FAILURE VOL. 8, NO. 9, 2020

Biomarkers in Amyloidosis SEPTEMBER 2020:701–11

T A B L E 4 Biomarkers in Cardiac Amyloidosis

First Author (Ref. #) Year Biomarker Amyloid Purpose or Clinical Implication

Dispenzieri et al. (4) 2003 cTnT/cTnI AL Evaluation of cTnT and cTnI as biochemical markers of cardiac dysfunction and
utility as prognostic indicators.
Palladini et al. (5) 2003 NT-proBNP AL Evaluation of NT-proBNP as a biochemical marker of cardiac dysfunction and
utility prognostic indicator.
Dispenzieri et al. (6) 2004 NT-proBNP, cTnT/cTnI AL Elevation of NT-proBNP and/or cTnT/cTnI in a prognostic staging system (Mayo
staging system).
Dispenzieri et al. (48) 2004 NT-proBNP, cTnT/cTnI AL Application of Mayo staging system with NT-proBNP and cTnT/cTnI to patients
undergoing PBSCT.
Palladini et al. (18) 2006 NT-proBNP AL Evaluation of NT-proBNP as an indicator of response to chemotherapy in patients
with AL.
Biolo et al. (44) 2008 MMPs, TIMPs, BNP AL and ATTR Differential increase in MMP-9 and TIMP-1 in AL vs. ATTR CA suggesting
underlying difference in cardiac ECM disruption. BNP elevation greater in AL CA.
Palladini et al. (19) 2010 NT-proBNP, hs-cTnT AL NT-proBNP predictive of response to treatment of cardiac AL. Potential increased
accuracy in prediction of OS with use of hs-cTnT.
Kastritis et al. (20) 2010 NT-proBNP AL NT-proBNP response associated with improved outcomes in patients with AL
treated with bortezomib.
Kristen et al. (42) 2010 hs-cTnT, NT-proBNP, cTnT AL Suggests that hs-cTnT could be very sensitive to the presence of cardiac
amyloidosis.
Palladini et al. (36) 2011 MR-proADM, NT-proBNP, AL MR-proADM was shown to be superior to NT-proBNP as a predictor of early death
cTnI using the Mayo staging system.
Kumar et al. (7) 2012 NT-proBNP, cTnT/cTnI AL Revised Mayo staging system using a higher cutoff for NT-proBNP and prior
threshold for cTnT/cTnI.
Palladini et al. (21) 2012 NT-proBNP, cTnT/cTnI AL NT-proBNP response identified as main criteria for defining cardiac response to
treatment. Elevation in cTnT/I post-treatment indicative of poorer outcome.
Ruberg et al. (27) 2012 NT-proBNP ATTR NT-proBNP levels increased in association with progression of ATTR (wt and V122I
mutation) CA. –TRACS
Castano et al. (23) 2012 BNP, cTnI ATTR Evaluation of baseline and follow-up BNP and cTnI for evidence of cardiac
response to treatment with diflunisal.
Obici et al. (31) 2012 NT-proBNP ATTR Evaluation baseline and follow-up NT-proBNP in response to treatment with
doxy/TUDCA.
Pinney et al. (51) 2013 NT-proBNP, cTnT ATTR Found that elevation in cTnT and, to a lesser degree, NT-proBNP was associated
with reduced OS in ATTRwt CA.
Wechalekar et al. (9) 2013 NT-proBNP, cTnT/cTnI AL Response to chemotherapy in patients with Mayo Stage III disease. NT-proBNP >
8,500 pg/ml is a poor prognostic indicator.
Tanaka et al. (45) 2013 MMPs, TIMPs, BNP, cTnI AL and ATTR The combination of MMP-2/TIMP-2, cTnI and BNP were highly discriminative for
differentiating between AL and ATTR CA. Elevated levels of MMP-2 and TIMP-1,
but not MMP-9 and TIMP-2 in AL CA.
Dispenzieri et al. (43) 2014 hs-cTnT, NT-proBNP, cTnT AL Hs-cTnT in place of cTn may simplify the prognostic algorithm by eliminating the
need for NT-proBNP in Mayo staging.
Kristen et al. (50) 2014 MR-proANP, NT-proBNP AL Demonstrated that MR-proANP performs equivalently to NT-proBNP in the Mayo
staging system.
Kastritis et al. (37) 2014 GDF-15, NT-proBNP, AL Findings suggest that GDF-15 levels in Q4 were discriminative in high-risk
hs-cTnT patients, identifying a sub-set with a median OS of 3 months.
Kristen et al. (39) 2014 OPN, NT-proBNP, cTnT AL Elevated OPN associated with poorer outcomes; may discriminate better between
high-risk patients when used with cTnT in the place of NT-proBNP.
Kastritis et al. (52) 2015 NT-proBNP, cTnT/cTnI AL NT-proBNP response post-treatment correlated to increased OS. Mayo staging
system and elevated NT-proBNP level pre-treatment used to successfully risk-
adapt the treatment regimen for increased 1-year OS in high-risk patients.
Sekijima et al. (24) 2015 BNP ATTR Evaluations of BNP at baseline and over a 1 to 2 yr follow-up-period in patients
treated with diflunisal.
Damy et al. (25) 2015 NT-proBNP, cTnI ATTR Evaluation of NT-proBNP and cTnI in ATTRm (non-V30M or V122I mutations)
treated with tafamidis.
Maurer et al. (26) 2015 NT-proBNP, cTnT/cTnI ATTR Evaluation of NT-proBNP and cTnT/I in patients with ATTRwt and known cardiac
disease treated with tafamidis.
Dispenzieri et al. (40) 2015 sST2, Gal-3, NT-proBNP, AL Findings showed sST2 demonstrated independent prognostic value on
cTnT multivariate modeling and may add additional prognostic information to
biomarker staging systems.
Kastritis et al. (41) 2015 OPG, NT-proBNP AL Elevation of OPG was correlated to NT-proBNP elevation and demonstrated
prognostic value independent of Mayo Stage. Q4 elevations associated with
median 1 yr. OS.
Gertz et al. (49) 2016 NT-proBNP AL Demonstrated NT-proBNP response as evidence of cardiac response to treatment
with NEOD001 an anti-LC antibody.
Connors et al. (53) 2016 BNP, cTnI ATTR BNP demonstrated prognostic significance in ATTRwt CA, cTnI did not show
significant correlation.
Continued on the next page
JACC: HEART FAILURE VOL. 8, NO. 9, 2020 Pregenzer-Wenzler et al. 707
SEPTEMBER 2020:701–11 Biomarkers in Amyloidosis

T A B L E 4 Continued

First Author (Ref. #) Year Biomarker Amyloid Purpose or Clinical Implication

Damy et al. (54) 2016 NT-proBNP, cTnT, hs-cTnT AL and ATTR NT-proBNP was a strong prognostic indicator in CA due to AL or ATTR. cTnT/hs-
cTnT was only prognostic in AL.
Grogan et al. (12) 2016 NT-proBNP, cTnT ATTR Defines staging system for ATTRwt based on the Mayo staging system for AL.
Perfetto et al. (55) 2016 NT-proBNP AL and ATTR Comparison of NT-proBNP levels in AL, ATTRwt, and ATTRm CA with similar
findings on ECHO. Identifies notable differences in NT-proBNP between all
3 types of CA.
Kristopher et al. (47) 2016 HGF, Gal-3 AL and ATTR Study looking to differentiate CA from systemic AL or other cardiomyopathies.
HGF elevation associated with both AL and ATTR CA, however also elevated in
HFrEF. Gal-3 only elevated in systemic AL, not AL CA.
Kastritis et al. (35) 2016 VWF, ADAMTS-13 AL High VWF levels demonstrated prognostic significance.
Wixner et al. (32) 2017 NT-proBNP ATTR Evaluation of NT-proBNP in patients with ATTR CA at baseline and during
treatment with doxy/UDCA.
Kristen et al. (56) 2017 NT-proBNP, cTnT/cTnI ATTR Demonstrates that Q4 elevations of NT-proBNP, cTnT and cTnI are independent
predictors of survival in ATTR.
Siepen et al. (57) 2017 NT-proBNP ATTR Identified NT-proBNP as an independent predictor of mortality in ATTRwt CA.
Takashio et al. (46) 2017 hs-cTnT, AL and ATTR Found hs-CTnT levels to be significantly higher in CA compared to other causes of
BNP cardiac hypertrophy
Gillmore et al. (13) 2017 NT-proBNP ATTR Defines staging system based on NT-proBNP and eGFR applicable to ATTRwt and
ATTRm
Hanson et al. (14) 2018 Serum TTR, cTnI ATTR Serum TTR levels for prognosis and response to therapy
Kastritis et al. (66) 2018 GDF-15 AL GDF-15 predicts mortality, progression to dialysis, and response to therapy
Adams et al. (33) 2018 NT-proBNP ATTR Clinical trial of patisiran in patients with ATTRm and neuropathy
Judge et al. (29) 2019 Serum TTR ATTR Serum TTR levels for in vivo response to therapy

ADAMTS-13 ¼ metalloproteinase with thrombospondin type-1 repeats 13; AL ¼ light chain amyloidosis; ATTR ¼ transthyretin amyloidosis; ATTRm ¼ hereditary transthyretin amyloidosis; ATTRwt ¼ wild-type
ATTR; CA ¼ cardiac amyloidosis; cTnI ¼ cardiac troponin I; cTnT ¼ cardiac troponin T; ECM ¼ extracellular matrix; Gal ¼ galactin; GDF ¼ growth differentiation factor; HFrEF ¼ heart failure with reduced
ejection fraction.; HGF ¼ hepatocyte growth factor; hs-cTn ¼ high sensitivity cardiac troponin; MMPs ¼ matrix metalloproteinases; MR-proADM ¼ midregional proadrenomedullin; MR-proANP ¼ midregional
pro-atrial natriuretic peptide; OPG ¼ osteoprotegerin; OPN ¼ osteopontin; PBSCT ¼ peripheral blood stem cell transplant; Q4 ¼ 4th fourth quartile; sST2 ¼ soluble suppression of tumorigenicity 2;
TIMPs ¼ tissue inhibitors of metalloproteinases; TRACS ¼ transthyretin amyloidosis cardiac study; TUDCA ¼ tauroursodeoxycholic acid; UDCA ¼ ursodeoxycholic acid; VWF ¼ von Willebrand factor; other
abbreviations as in Tables 1 to 3.

echogenic evidence of cardiac response, defined as a
2-mm reduction in interventricular septal thickness
in response to treatment, was not associated with a
survival benefit and that increases in cTnT/I of >33%
post-treatment are predictive of poorer outcomes
(21). The findings of this study contributed signifi-
cantly to the 2012 consensus guidelines for treatment
of AL that were updated to include the use of cardiac
biomarkers for quantification of cardiac response
(NT-proBNP) or progression of cardiac involvement
(NT-proBNP or cTnT/I) (Table 3) (16).
ASSESSMENT OF THERAPEUTIC RESPONSE
ATTR. Several new therapies aimed at the reduction,
stabilization, or degradation of TTR have emerged
recently (22). Cardiac biomarkers, mainly NT-proBNP,
along with imaging and clinical symptoms have been
used in clinical trials in an effort to quantify the impact
of a few of these new therapies on cardiac function.
TTR protein stabilizers, such as diflunisal, tafami-
dis, and AG-10, are medications directed at the
stabilization of the TTR tetramer (2). Three small,
single-arm clinical trials have searched for evidence of
the efficacy of diflunisal, 250 mg twice daily, in ATTR
cardiac amyloidosis using cardiac biomarkers. The first
of those studies, published in 2012 (23) analyzed BNP
and cTnI in 12 patients with ATTRwt or ATTRm at
baseline and at 1 year. In that population, there was a
small upward trend in both BNP and cTnI over the
course of treatment without associated changes in
cardiac structure or function (23). The results of the
second study, published in 2015 (24), which monitored
cardiac parameters, including BNP, in 28 Japanese
patients with ATTRm over a minimum of 12 months,
demonstrated nonsignificant fluctuations in BNP over
the follow-up period and evidence of slow clinical
deterioration in cardiac function over approximately 2
years (24). More promising are the results of the third
IN study, published in 2018, which showed that, in 12
patients with ATTRwt treated with diflunisal, the
levels of serum TTR were higher and the cTnI levels
remained stable after 2 years of therapy compared to
those in 23 untreated patients (14).
The efficacy of tafamidis, 20 mg once daily, in
treating amyloid cardiomyopathy was assessed by
using cardiac biomarkers in 2 small, single-arm clinic
trials, both of which were published in 2015. The first of
those studies (25) presented post hoc analysis of an
open-label study that monitored cardiac parameters in
21 patients with ATTRm (excluding p.Val50Met
[V30M] and V122I mutations). That study did not
demonstrate any significant change in NT-proBNP
708 Pregenzer-Wenzler et al.
Biomarkers in Amyloidosis
over the course of 12 months of treatment in patients
presenting with either elevated or normal NT-proBNP
levels. cTnI remained stable over the course of the
study (25). The second study (26) included both pa-
tients with ATTRwt and those with ATTRm with the
V122I mutation. However, the results were only re-
ported for the 31 patients with ATTRwt. There was a
nonsignificant elevation in NT-proBNP and an average
increase in cTnT/I in that population after 12 months of
treatment with tafamidis. In the absence of a control
group, biomarker results were compared to those re-
ported for the patients with ATTRwt in the TRACS
(Transthyretin Amyloidosis Cardiac Study) observa-
tional cohort (27), which had demonstrated a larger,
increase in NT-proBNP over a similar time period and
indicated that tafamidis was able to slow progression
of cardiac disease (26). Recently, the results of the first
phase III study of tafamidis (ATTR-ACT [Tafamidis in
Transthyretin Cardiomyopathy Clinical Trial]) were
published. The multicenter trial randomized 264 pa-
tients with ATTR amyloidosis (wild-type and mutant)
to receive either 80 mg of tafamidis, 20 mg of tafami-
dis, or placebo in ratio of 2:1:2 for 30 months. Tafamidis
demonstrated a significant reduction in all-cause
mortality compared to placebo (29.5% vs. 42.9%) and
a significant reduction of cardiovascular related hos-
pitalizations (0.48 per year vs. 0.70 per year, respec-
tively). These outcomes were calculated using
aggregate data for the 2 doses and prespecified anal-
ysis of 80 versus 20 mg showed similar benefits. In
relation to biomarkers, the study found that the pa-
tients who received tafamidis had lower elevations
(least squares mean differences) in NT-proBNP than
those who received placebo at months 12 (735.14) and
30 (2,180.54), suggesting a sustained biologic effect
over time related to tafamidis (28).
AG-10 is a new TTR stabilizer that was tested in a
phase II clinical trial in 49 patients with ATTR car-
diomyopathy (wild type or mutant). Subjects were
randomized to receive 400 mg or 800 mg or placebo
in 1:1:1 ratio. Subjects taking AG10 achieved more
than 90% stabilization of the tetrater with satisfac-
tory safety and tolerability. The study measured
serum TTR levels (pre-albumin) as a surrogate
endpoint for in vivo response to therapy. At day 28,
patients receiving 400 and 800 mg of AG-10 had
higher levels of 36% and 50% TTR, respectively; but
patients taking placebo experienced a reduction of 7%
(29). Similar to the measurement of levels of diflu-
nisal (14), serum levels of TTR have the potential to
become a cost-effective method to assess response to
therapy in patients with ATTR amyloidosis (30).
Amyloid degraders, such as the combination ther-
apy of doxycycline and secondary bile acids are
JACC: HEART FAILURE VOL. 8, NO. 9, 2020
SEPTEMBER 2020:701–11
hypothesized to act synergistically to reduce deposi-
tion of TTR and degrade the TTR amyloid matrix
already deposited in tissues. The first clinical trial to
assess the efficacy of this class of therapy on ATTR
cardiac amyloidosis was a small, phase II, open-label
study using doxycycline and tauroursodeoxycholic
acid (TUDCA) (31). Only 7 patients completed the full
12 months, and all of those patients had evidence of
cardiac involvement at baseline. NT-proBNP levels
increased in 3 patients and remained stable in 4, and
no patients exhibited clinical evidence of cardiac
progression (31). Another phase II study (32) pub-
lished in 2017 evaluated the combination of doxycy-
cline and ursodeoxycholic acid (UDCA) in patients
with known ATTR cardiac amyloidosis; however, in
that study, doxycycline was intermittently dis-
continued for periods of 2 weeks after every 4 weeks
of treatment. Only 14% of the initial 28 patients
completed the study. NT-proBNP levels remained
stable for the first 6 months but rose significantly at 1
year. Participation in the study was terminated early
for 14% of patients due to treatment failure, which
was defined as a 30% increase in NT-proBNP from
baseline (32).
Recent publications with TTR gene silencers have
provided encouraging results for cardiac response to
therapy. The APOLLO study, published in 2018, ran-
domized 225 patients with ATTRm and poly-
neuropathy to patisiran therapy, 0.3 mg/kg or placebo
once every 3 weeks. That study demonstrated a sig-
nificant improvement in neuropathy and quality of
life; and in a subgroup of patients with cardiac
involvement, there was a decrease in the NT-proBNP-
to-baseline ratio of 0.89 in the patisiran arm at
18 months compared to 1.89 in the placebo group,
suggesting improved cardiac function (33). A subse-
quent publication focused on the outcomes in 126
patients with cardiac involvement defined as patients
with left ventricular wall thickness $13 mm and no
history of aortic valve disease or hypertension. In that
cardiac population, patients taking patisiran had a
55% reduction in NT-proBNP at 18 months compared
to placebo (a fold-change patisiran-to-placebo ratio of
0.45; 95% confidence interval: 0.34 to 0.59; p ¼ 7.7 
108 (34).
NOVEL BIOMARKERS IN AL AND ATTR. At least 10
other novel biomarkers have been studied in patients
with cardiac amyloidosis (Table 4). Of the biomarkers
evaluated, preliminary studies suggest that von Wil-
lebrand factor (35), mid-regional pro-adrenomedullin
(36), growth differentiation factor-15 (37,38), osteo-
pontin (39), soluble suppression of tumorigenicity 2
(40), and osteoprotegerin (41) may be able to improve
JACC: HEART FAILURE VOL. 8, NO. 9, 2020
SEPTEMBER 2020:701–11
prognostication in high-risk patients with AL cardiac
amyloidosis when substituted
conjunction with the existing Mayo staging systems.
Preliminary studies also suggested
sensitivity cardiac troponin T (hs-cTnT) had the po-
tential to improve the sensitivity of the Mayo staging
system (19,42). Although the most recent study did not
show that hs-cTnT was able to contribute additional
prognostic information to the existing staging sys-
tems, it did demonstrate its potential to simplify the
prognostic algorithm by replacing the combination of
NT-proBNP and a cardiac troponin in the Mayo staging
system (43). Additional areas of study in cardiac
amyloidosis using novel biomarkers include the eval-
uation of matrix metalloproteinases and tissue in-
hibitors of metalloproteinases
between AL and ATTR cardiac amyloidosis (44,45) and
the use of both hs-cTnT (46) and hepatocyte growth
factor (47) to differentiate between cardiac amyloid-
osis and other causes of cardiomyopathy (38).
CONCLUSION AND FUTURE PROSPECTS
In AL cardiac amyloidosis, cardiac biomarkers have
been used successfully to develop staging systems that
have been consistently validated in predicting base-
line prognosis at time of diagnosis and have demon-
strated utility in predicting prognosis in response to
treatment (6,7,48). In addition, NT-proBNP has been
successfully established and validated as a surrogate
marker for survival in AL based on treatment response
(21,49). As advances in disease-modifying therapies
continue to be developed and as ATTR cardiac
amyloidosis has become an increasingly recognized
cause of diastolic dysfunction in our aging population,
the need for methods of early accurate diagnosis, risk
stratification, and assessment of therapeutic response
for cardiac amyloidosis will continue to grow. Cardiac
biomarkers provide a noninvasive, easily accessible,
relatively inexpensive method for evaluating cardiac
disease and its progression, and have the potential to
take on a more expansive role in the diagnosis and
ongoing assessment of cardiac amyloidosis.
REFERENCES
1. Merlini G, Bellotti V. Molecular mechanisms of
amyloidosis. N Engl J Med 2003;349:583–96.
2. Patel KS, Hawkins PN. Cardiac amyloidosis:
where are we today? J Intern Med 2015;278:
126–44.
3. Jaffe AS, Ravkilde J, Roberts R, et al. It’s time
for a change to a troponin standard. Circulation
2000;102:1216–20.
4. Dispenzieri A, Kyle RA, Gertz MA, et al. Survival
in patients with primary systemic amyloidosis and
Pregenzer-Wenzler et al. 709
Biomarkers in Amyloidosis
Review of how cardiac biomarkers have been used
for or used in and studied in patients with cardiac amyloidosis re-
veals the need for continued investigation in a num-
that high- ber of areas. Further risk stratification of patients
with high-risk (Mayo Stages 3b and IV) AL cardiac
amyloidosis is needed to direct and, if necessary, risk-
adapt prompt therapeutic interventions. The addition
of a higher NT-proBNP threshold or the use of a novel
cardiac biomarker to further refine the Mayo staging
system has been explored (19,36,37,39,41–43,50).
Furthermore, the effects of atrial fibrillation and renal
failure in the Mayo staging system require further
investigation. Additionally, new treatment options
for ATTR underscore the need for further evaluation
of how cardiac biomarkers reflect prognosis and dis-
to differentiate ease progression in ATTRwt and ATTRm cardiac
amyloidosis to determine whether these biomarkers
are accurate indicators of treatment response.
Further delineation of how the natural history and
the differences between ATTRwt and ATTRm are
defined by cardiac biomarkers is necessary to better
understand the implication of post-treatment cardiac
biomarker levels (23–26,31,32). Finally, the recogni-
tion of ATTR cardiac amyloidosis as an under-
diagnosed, treatable cause of diastolic heart failure,
the significant difference in treatment of AL and
ATTR, and the rapidly progressive nature of AL car-
diac amyloidosis identify the need for simple,
noninvasive methods of differentiating AL and ATTR
cardiac amyloidosis from each other and from other
causes of diastolic heart failure (44–46). As the diag-
nosis and treatment of cardiac amyloidosis continue
to evolve rapidly, the use of cardiac biomarkers in
this progressive, fatal disease process remains
an exciting, clinically relevant area of active
investigation.
ADDRESS FOR CORRESPONDENCE: Dr. Jose Nativi-
Nicolau, Cardiac Amyloidosis Program, University
of Utah School of Medicine, 50 North Medical
Drive, Salt Lake City, Utah 84132. E-mail: jose.
nativi@hsc.utah.edu.
raised serum cardiac troponins. Lancet 2003;361: systemic amyloidosis. J Clin Oncol 2004;22:
1787–9. 3751–7.
5. Palladini G, Campana C, Klersy C, et al. 7. Kumar S, Dispenzieri A, Lacy MQ, et al.
Serum N-terminal pro-brain natriuretic pep- Revised prognostic staging system for
tide is a sensitive marker of myocardial light chain amyloidosis incorporating cardiac
dysfunction in AL amyloidosis. Circulation biomarkers and serum free light
2003;107:2440–5. chain measurements. J Clin Oncol 2012;30:
989–95.
6. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum
cardiac troponins and N-terminal pro-brain 8. Kumar SK, Gertz MA, Dispenzieri A. Validation
natriuretic peptide: a staging system for primary of Mayo Clinic staging system for light chain
710 Pregenzer-Wenzler et al.
Biomarkers in Amyloidosis
amyloidosis with high-sensitivity troponin. J Clin
Oncol 2019;37:171–3.
9. Wechalekar AD, Schonland SO, Kastritis E, et al.
A European collaborative study of treatment
outcomes in 346 patients with cardiac stage III AL
amyloidosis. Blood 2013;121:3420–7.
10. Palladini G, Foli A, Milani P, et al. Best use of
cardiac biomarkers in patients with AL amyloidosis
and renal failure. Am J Hematol 2012;87:465–71.
11. Dittrich T, Benner A, Kimmich C, et al. Perfor-
mance analysis of AL amyloidosis cardiac
biomarker staging systems with special focus on
renal failure and atrial arrhythmia. Haematologica
2019;104:1451–9.
12. Grogan M, Scott CG, Kyle RA, et al. Natural
history of wild–type transthyretin cardiac
amyloidosis and risk stratification using a novel
staging system. J Am Coll Cardiol 2016;68:
1014–20.
13. Gillmore JD, Damy T, Fontana M, et al. A new
staging system for cardiac transthyretin amyloid-
osis. Eur Heart J 2017;39:2799–806.
14. Hanson JLS, Arvanitis M, Koch CM, et al. Use of
serum transthyretin as a prognostic indicator and
predictor of outcome in cardiac amyloid disease
associated with wild-type transthyretin. Circ Heart
Fail 2018;11:e004000.
15. Apple FS, Ler R, Murakami MM. Determination
of 19 cardiac troponin I and T assay 99th percen-
tile values from a common presumably healthy
population. Clin Chem 2012;58:1574–81.
16. Comenzo RL, Reece D, Palladini G, et al.
Consensus guidelines for the conduct and report-
ing of clinical trials in systemic light-chain
amyloidosis. Leukemia 2012;26:2317–25.
17. Merlini G, Lousada I, Ando Y, et al. Rationale,
application and clinical qualification for
NT-proBNP as a surrogate end point in pivotal
clinical trials in patients with AL amyloidosis.
Leukemia 2016;30:1979–86.
18. Palladini G, Lavatelli F, Russo P, et al. Circu-
lating amyloidogenic free light chains and serum
N-terminal natriuretic peptide type B decrease
simultaneously in association with improvement of
survival in AL. Blood 2006;107:3854–8.
19. Palladini G, Barassi A, Klersy C, et al. The
combination of high-sensitivity cardiac troponin T
(hs-cTnT) at presentation and changes in N-ter-
minal natriuretic peptide type B (NT-proBNP) after
chemotherapy best predicts survival in AL
amyloidosis. Blood 2010;116:3426–30.
20. Kastritis E, Wechalekar AD, Dimopoulos MA,
et al. Bortezomib with or without dexamethasone
in primary systemic (light chain) amyloidosis.
J Clin Oncol 2010;28:1031–7.
21. Palladini G, Dispenzieri A, Gertz MA, et al. New
criteria for response to treatment in immuno-
globulin light chain amyloidosis based on free
light chain measurement and cardiac biomarkers:
impact on survival outcomes. J Clin Oncol 2012;
30:4541–9.
22. Dubrey S, Ackermann E, Gillmore J. The
transthyretin amyloidoses: advances in therapy.
Postgrad Med J 2015;91:439–48.
23. Castano A, Helmke S, Alvarez J, Delisle S,
Maurer MS. Diflunisal for ATTR cardiac amyloid-
osis. Congest Heart Fail 2012;18:315–9.
24. Sekijima Y, Tojo K, Morita H, Koyama J,
Ikeda S. Safety and efficacy of long–term diflunisal
administration in hereditary transthyretin (ATTR)
amyloidosis. Amyloid 2015;22:79–83.
25. Damy T, Judge DP, Kristen AV, Berthet K, Li H,
Aarts J. Cardiac findings and events observed in an
open-label clinical trial of tafamidis in patients
with non-Val30Met and non-Val122Ile hereditary
transthyretin amyloidosis. J Cardiovasc Transl Res
2015;8:117–27.
26. Maurer MS, Grogan DR, Judge DP, et al.
Tafamidis in transthyretin amyloid cardiomyopa-
thy: effects on transthyretin stabilization and
clinical outcomes. Circ Heart Fail 2015;8:519–26.
27. Ruberg FL, Maurer MS, Judge DP, et al. Pro-
spective evaluation of the morbidity and mortality
of wild-type and V122I mutant transthyretin am-
yloid cardiomyopathy: the Transthyretin
Amyloidosis Cardiac Study (TRACS). Am Heart J
2012;164:222–8.
28. Maurer MS, Schwartz JH, Gundapaneni B, et al.
Tafamidis treatment for patients with trans-
thyretin amyloid cardiomyopathy. N Engl J Med
2018;379:1007–16.
29. Judge DP, Heitner SB, Falk RH, et al. Trans-
thyretin stabilization by AG10 in symptomatic
transthyretin amyloid cardiomyopathy. J Am Coll
Cardiol 2019;74:285–95.
30. Nativi-Nicolau J. Serum transthyretin: predic-
tor of amyloidosis outcomes? Circ Heart Fail 2018;
11:e004802.
31. 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.
32. Wixner J, Pilebro B, Lundgren HE, Olsson M,
Anan I. Effect of doxycycline and ursodeoxycholic
acid on transthyretin amyloidosis. Amyloid 2017;
24:78–9.
33. Adams D, Gonzalez-Duarte A, O’Riordan WD,
et al. Patisiran, an RNAi therapeutic, for hereditary
transthyretin amyloidosis. N Engl J Med 2018;379:
11–21.
34. Scott D, Solomon DA, Arnt K, et al. Effects of
patisiran, an RNA interference therapeutic, on
cardiac parameters in patients with hereditary
transthyretin-mediated amyloidosis: an analysis of
the APOLLO study. Circulation 2018;139:431–43.
35. Kastritis E, Papassotiriou I, Terpos E, et al.
Clinical and prognostic significance of serum levels
of von Willebrand factor and ADAMTS-13 antigens
in AL amyloidosis. Blood 2016;128:405–9.
36. Palladini G, Barassi A, Perlini S, et al. Midre-
gional proadrenomedullin (MR-proADM) is a
powerful predictor of early death in AL amyloid-
osis. Amyloid 2011;18:216–21.
37. Kastritis E, Papassotiriou I, Terpos E, et al.
Growth differentiation factor-15 in patients with
light chain (AL) amyloidosis has independent
prognostic significance and adds prognostic in-
formation related to risk of early death and renal
outcomes. Blood 2014;124.
JACC: HEART FAILURE VOL. 8, NO. 9, 2020
SEPTEMBER 2020:701–11
38. Kastritis E, Papassotiriou I, Merlini G, et al.
Growth differentiation factor-15 is a new
biomarker for survival and renal outcomes in light
chain amyloidosis. Blood 2018;131:1568–75.
39. Kristen AV, Rosenberg M, Lindenmaier D, et al.
Osteopontin: a novel predictor of survival in pa-
tients with systemic light-chain amyloidosis. Am-
yloid 2014;21:202–10.
40. Dispenzieri A, Gertz MA, Saenger A, et al.
Soluble suppression of tumorigenicity 2 (sST2),
but not galactin-3, adds to prognostication in
patients with systemic AL amyloidosis indepen-
dent of NT-proBNP and troponin T. Am J Hematol
2015;90:524–8.
41. Kastritis E, Gavriatopoulou M, Dimopoulos MA,
et al. Osteoprotegerin is a significant prognostic
factor for overall survival in patients with primary
systemic amyloidosis independent of the Mayo
staging. Blood Cancer J 2015;5:e319.
42. Kristen AV, Giannitsis E, Lehrke S, et al.
Assessment of disease severity and outcome in
patients with systemic light-chain amyloidosis by
the high-sensitivity troponin T assay. Blood 2010;
116:2455–61.
43. Dispenzieri A, Gertz MA, Kumar SK, et al. High
sensitivity cardiac troponin T in patients with
immunoglobulin light chain amyloidosis. Heart
2014;100:383–8.
44. Biolo A, Ramamurthy S, Connors LH, et al.
Matrix metalloproteinases and their tissue in-
hibitors in cardiac amyloidosis: relationship to
structural, functional myocardial changes and to
light chain amyloid deposition. Circ Heart Fail
2008;1:249–57.
45. Tanaka K, Essick EE, Doros G, et al. Circulating
matrix metalloproteinases and tissue inhibitors of
metalloproteinases in cardiac amyloidosis. J Am
Heart Assoc 2013;2:e005868.
46. Takashio S, Yamamuro M, Izumiya Y, et al.
Diagnostic utility of cardiac troponin T level in
patients with cardiac amyloidosis. ESC Heart Fail
2017;5:27–35.
47. Swiger KJ, Friedman EA, Brittain EL, et al.
Plasma hepatocyte growth factor is a novel marker
of AL cardiac amyloidosis. Amyloid 2016;23:
242–8.
48. Dispenzieri A, Gertz MA, Kyle RA, et al.
Prognostication of survival using cardiac troponins
and N-terminal pro-brain natriuretic peptide in
patients with primary systemic amyloidosis un-
dergoing peripheral blood stem cell trans-
plantation. Blood 2004;104:1881–7.
49. Gertz MA, Landau HJ, Weiss BM. Organ
response in patients with AL amyloidosis treated
with NEOD001, an amyloid–directed monoclonal
antibody. Am J Hematol 2016;91:E506–8.
50. Kristen AV, Biener M, Hegenbart U, et al.
Evaluation of the clinical use of midregional
pro-atrial natriuretic peptide (MR-proANP) in
comparison to N-terminal pro-B-type natriuretic
peptide (NT-proBNP) for risk stratification in pa-
tients with light-chain amyloidosis. Int J Cardiol
2014;176:1113–5.
51. Pinney JH, Whelan CJ, Petrie A, et al. Senile
systemic amyloidosis: clinical features at
JACC: HEART FAILURE VOL. 8, NO. 9, 2020
SEPTEMBER 2020:701–11
presentation and outcome. J Am Heart Assoc
2013;2:e000098.
52. Kastritis E, Roussou M, Gavriatopoulou M,
et al. Long-term outcomes of primary sys-
temic light chain (AL) amyloidosis in
patients treated upfront with bortezomib or
lenalidomide and the importance of risk
adapted strategies. Am J Hematol 2015;90:
E60–5.
53. Connors LH, Sam F, Skinner M, et al. Heart
failure resulting from age-related cardiac amyloid
disease associated with wild-type transthyretin: a
prospective, observational cohort study. Circula-
tion 2016;133:282–90.
54. Damy T, Jaccard A, Guellich A, et al. Identifi-
cation of prognostic markers in transthyretin and
AL cardiac amyloidosis. Amyloid 2016;23:
194–202.
55. Perfetto F, Bergesio F, Grifoni E, et al.
Different NT-proBNP circulating levels for
different types of cardiac amyloidosis.
J Cardiovasc Med 2016;17:810–7.
Pregenzer-Wenzler et al. 711
Biomarkers in Amyloidosis
56. Kristen AV, Maurer MS, Rapezzi C, et al. Impact
of genotype and phenotype on cardiac biomarkers in
patients with transthyretin amyloidosis—report from
the Transthyretin Amyloidosis Outcome Survey
(THAOS). PLoS One 2017;12:e0173086.
57. Siepen FAD, Bauer R, Voss A, et al. Predictors of
survival stratification in patients with wild-type car-
diac amyloidosis. Clin Res Cardiol 2017;107:158–69.
KEY WORDS amyloidosis, biomarkers, light
chains, transthyretin