JACC: HEART FAILURE VOL. -, NO.

-, 2020
PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION

STATE-OF-THE-ART PAPER

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;-:-–-) 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
of cause, the degree of cardiac involvement at the
time of diagnosis is the most important prognostic
indicator.
The purpose of this review was to summarize the
amyloidosis that are commonly associated with car- history and current clinical use of cardiac biomarkers
diac involvement are acquired monoclonal immuno- for assessment of prognosis and response to therapy
globin light chain amyloidosis (AL), wild-type in cardiac amyloidosis (Central Illustration) and to
transthyretin amyloidosis (ATTRwt), and hereditary describe the ongoing areas of investigation into car-
transthyretin amyloidosis (ATTRm) (2). Regardless diac amyloidosis.

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. Dr. Nativi-Nicolau 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

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ABBREVIATIONS CARDIAC BIOMARKERS FOR STAGING using high-sensitivity cTnT, however a cutoff of 40
AND ACRONYMS AND PROGNOSIS pg/ml is recommended (8).
A few studies have gone on to analyze the prog-
ADAMTS-13 =
metalloproteinase with
STAGING OF AL. The prognosis of patients nostic value of the Mayo staging system in patients
thrombospondin type-1 repeats with AL is highly dependent on the extent of undergoing treatment for AL. Wechalekar et al. (9)
13 evaluated the outcomes in response to chemotherapy
cardiac involvement at the time of diagnosis.
AL = light chain amyloidosis Given that cardiac troponins T (cTnT) and I in a large cohort of patients classified as Stage III by
ATTR = transthyretin (cTnI) have been shown to be both sensitive the original Mayo staging system. The investigators’
amyloidosis
and specific markers of cardiac injury (3), results, published in 2013, demonstrated a median OS
ATTRwt = wild-type Dispernzieri et al. (4) reported that patients of 7.1 months and identified an ultra-high risk popu-
transthyretin amyloidosis
with detectable cTnT or cTnI at diagnosis of lation (MAYO3b) characterized by NT-proBNP con-
ATTRm = mutant transthyretin
AL had a median observed survival (OS) of 6 centrations of >8,500 ng/l and troponin-T >0.035 m g/l
amyloidosis
to 8 months compared to a median OS of (Table 1), with an OS of only 5 months (Figure 2B) (9).
BNP = B-type natriuretic
peptide approximately 21 months in patients with The staging systems in AL amyloidosis have been
CA = cardiac amyloidosis
undetectable troponin levels. At the same accepted for prognosis in clinical practice; however,
time, Palladini et al. (5) analyzed the further research is required in specific populations,
cTn = cardiac troponin
expression of N-terminal pro–B-type natri- such as patients with atrial fibrillation, who are
cTnI = cardiac troponin I
uretic peptide (NT-proBNP) in patients newly known to have elevated natriuretic peptides. Also,
cTnT = cardiac troponin T
diagnosed with AL and found a correlation the natriuretic peptides are cleared by the kidneys,
ECM = extra cellular matrix
between elevated NT-proBNP levels and and their levels are affected by the glomerular filtra-
eGFR = estimated glomerular
both clinical cardiac involvement and tion rate. Palladini et al. (10) demonstrated that, in
filtration rate
decreased OS. patients with AL amyloidosis with an estimated
Gal-3 = galactin-3
A staging system for AL amyloidosis was glomerular filtration rate (eGFR) of <15 ml/
GDF-15 = growth
developed in 2004 by using patients with min/1.73 m 2, NT-proBNP loses its prognostic value,
differentiation factor-15
newly diagnosed AL seen at the Mayo Clinic whereas the B-type natriuretic peptide still predicts
HFrEF = heart failure with
reduced ejection fraction between 1979 and 2000. This system, later survival. A study in 1,224 patients by Dittirch et al. (11)
hs-cTn = high-sensitivity
termed the MAYO2004 staging system, from the Heidelberg Center, compared the perfor-
cardiac troponin defined patients as Stages I to III based on mance of all AL staging systems in patients with atrial
HGF = hepatocyte growth the absence of elevated cardiac biomarker fibrillation and in patients with an eGFR <50. They
factor (Stage I) versus the presence of a single found that MAYO2004, MAYO2012, and MAYO3b
MMPs = matrix elevated cardiac biomarker, cTnT/cTnI or performance remained significant in patients with
metalloproteinases
NT-proBNP (Stage II) versus the elevation of eGFR <50. However, the performance of all of them is
MR-proADM = mid-regional both cardiac biomarkers (Stage III), with a reduced in patients with atrial fibrillation but less
pro-adrenomedullin
median OS of approximately 27, 11, and affected in patients assessed using the MAYO3b sys-
MR-proANP = midregional
4 months, respectively (p < 0.0001) (6). For tem. These findings favor the MAYO3b system in pa-
pro-atrial natriuretic peptide
this staging system, the threshold values of tients with eGFR <50 and in patients with atrial
NT-proBNP = N-terminal pro–
B-type natriuretic peptide cardiac biomarkers were set at the lower fibrillation.
NYHA = New York Heart
limit of detection for cTnT at <0.035 mg/l, STAGING OF ATTR. In 2016, Grogan et al. (12) re-
Association detection of cTnI at <0.1 m g/l, and at the ported a retrospective review of patients with
OPN = osteopontin upper limit of normal for NT-proBNP ATTRwt between 1965 and 2013 to explore cTnT and
OPG = osteoprotegerin at <332 ng/l (Table 1) (6). The MAYO2004 NT-proBNP as predictors of survival. Based on their
PBSCT = peripheral blood stem
staging system was revised and expanded in findings, a staging system was proposed that uses the
cell transplant 2012 (MAYO2012) to include a third inde- same Stages I to III, defined in the Mayo staging sys-
sST2 = soluble suppression of pendent prognostic indicator of OS, the tem for AL, based on the presence or absence of
tumorigenicity 2 clonal free light chain burden difference elevation in cTnT and/or NT-proBNP. The ATTRwt
TIMPs = tissue inhibitors of of $18 mg/dl. This allowed for Stages I to IV staging system uses a cutoff point for cTnT
metalloproteinases
with a median OS of approximately 94, 40, of $0.05 ng/ml; however, the cutoff value for NT-
TUDCA = tauroursodeoxycholic 14, and 6 months, respectively (p < 0.001) proBNP determined to be prognostic in ATTRwt was
acid
(Figure 2A) (7). In the MAYO2012 staging significantly higher, at 3,000 pg/ml, than the cutoff
UDCA = ursodeoxycholic acid
system, the cutoff value for NT-proBNP was point of 1,800 pg/ml used by the revised Mayo staging
VWF = von Willebrand factor
1,800 pg/ml, and the cutoff for cTnT system for AL (Table 2). The present study found a
was $0.025 ng/ml (Table 1) (7). The median OS of 66, 40, and 20 months for Stages I, II,
MAYO2012 system can also be calculated and III, respectively (Figure 2C) (12).
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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).

Until very recently, no formal staging system had optimal cutoff point for NT-proBNP was 3,000 pg/ml
been proposed for ATTRm cardiac amyloidosis. In and 45 ml/min/1.73 m 2 for eGFR. It defines Stages I
2017, Gillmore et al. (13) proposed a staging system (NT-proBNP and eGFR less than or equal to the cutoff
based on NT-proBNP and eGFR that used retrospec- point) to III (both NT-proBNP and eGFR above the
tive analysis of a mixed population of patients with cutoff point) (Table 2), with OS of the combined
ATTR cardiac amyloidosis identified as having cohort for Stages I, II, and III as approximately 62, 47,
ATTRwt, p.Val142Ile (V122I) ATTRm or other ATTRm and 24 months, respectively (Figure 2D). Although
(13). Similar to the staging system proposed by Grogan this staging system is presented as being applicable to
et al. (12), the study by Gillmore found that the 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 Wild-Type & Mutant ATTR Amyloidosis
- NT-proBNP - NT-proBNP
- cTnT/cTnl - cTnT/cTnl
- Serum free light chains - Serum transthyretin levels (pre-albumin)
Cardiac Amyloidosis

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

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.
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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).
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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) ATTRm NT-proBNP $ 3,000 ng/l Stage I ¼ NT-proBNP #3,000 ng/l and Stage I ¼ 69 m
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 response to treatment. The first of these studies, a
associated with a shorter OS in all 3 stages; however, prospective study published in 2006, demonstrated
this mutation is predominant in some ethnic groups, both clinical improvement in heart failure symptoms
and the shorter survival could result from multiple and prolonged median OS in patients who achieved
factors besides genotype (13). both an NT-proBNP and a hematologic response
Serum transthyretin (TTR), also known as pre- following 3 cycles of chemotherapy, whereas patients
albumin, is another biomarker that has been evalu- who had progression of NT-proBNP levels did not
ated for prognosis. In a recent study by Hanson et al. receive clinical or survival benefits, despite a
(14), patients with ATTRwt with low serum levels of demonstrated hematologic response (18). These
TTR <18 mg/dl (normal range, 18 to 45 mg/dl) had a findings were confirmed in larger, retrospective
median survival of 2.8 years, compared to 4.1 years in studies published in 2010. One of those studies
patients with serum TTR levels above the cutoff. examined specifically NT-proBNP levels at 6 months
There are some considerations for the interpreta- in response to various treatment regimens (19), and
tion of cardiac troponins. Biomarker cTnI has several another study aimed specifically at evaluating the
manufacturers and essays that are not harmonized, efficacy of bortezomib in treatment of AL (20). Later,
and the results are not comparable among the essays. in response to the need for updated criteria to assess
In contrast, cTnT essays are developed from only 1 hematologic and cardiac response to the treatment of
manufacturer and have good standardization, making AL, a consensus paper described updated criteria to
results comparable among them. High-sensitivity assess hematologic and cardiac response to treatment
troponin essays were introduced for earlier detec- of AL amyloidosis (21). The criteria were based on
tion of myocardial injury; however, they require data from European and U.S. centers and validated in
specific cutoff values based on sex, and healthy in- the cohort studied by Palladini et al. (10). That study
dividuals can have small undetectable levels (15). demonstrated that a 30% reduction in the NT-proBNP
levels in response to treatment is the best indicator of
CARDIAC BIOMARKERS FOR ASSESSMENT OF
cardiac response and strongly correlated to increase
RESPONSE TO THERAPY
median OS. In addition, that report showed that

ASSESSMENT OF THERAPEUTIC RESPONSE IN

AL. The potential utility of NT-proBNP as a tool to
T A B L E 3 Biomarkers for Therapeutic Response in AL Amyloidosis
assess response to therapy for patients with AL was
Heart response
alluded to in the first study by Palladini et al. (5),
1. NT-proBNP response (>30% and >300 ng/l decrease in patients with baseline
which showed that most patients with elevated NT-proBNP $650 ng/l) or
NT-proBNP levels at diagnosis who achieved hema- 2. NYHA functional class response ($2 class decrease in subjects with baseline NYHA functional
tologic response to treatment also demonstrated a class III or IV)
Heart progression
significant reduction in their NT-proBNP levels. Since
1. NT-proBNP progression (>30% and >300 ng/l increase*) or
that time, several studies of patients receiving treat-
2. cTn progression ($33% increase), or
ment for AL have demonstrated a significant 3. Ejection fraction progression ($10% decrease)
correlation between a defined decrease in NT-proBNP
(NT-proBNP response) (16) and increased overall Table adapted with permission from Comenzo et al. (16). *Patients with progressively worsening renal function
were not scored for NT-proBNP progression.
survival in response to therapy (17), confirming the NYHA ¼ New York Heart Association; other abbreviations as in Tables 1 and 2.
utility of cardiac biomarkers in the assessment of
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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
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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 and cTnI in 12 patients with ATTRwt or ATTRm at
2-mm reduction in interventricular septal thickness baseline and at 1 year. In that population, there was a
in response to treatment, was not associated with a small upward trend in both BNP and cTnI over the
survival benefit and that increases in cTnT/I of >33% course of treatment without associated changes in
post-treatment are predictive of poorer outcomes cardiac structure or function (23). The results of the
(21). The findings of this study contributed signifi- second study, published in 2015 (24), which monitored
cantly to the 2012 consensus guidelines for treatment cardiac parameters, including BNP, in 28 Japanese
of AL that were updated to include the use of cardiac patients with ATTRm over a minimum of 12 months,
biomarkers for quantification of cardiac response demonstrated nonsignificant fluctuations in BNP over
(NT-proBNP) or progression of cardiac involvement the follow-up period and evidence of slow clinical
(NT-proBNP or cTnT/I) (Table 3) (16). deterioration in cardiac function over approximately 2
years (24). More promising are the results of the third
ASSESSMENT OF THERAPEUTIC RESPONSE IN study, published in 2018, which showed that, in 12
ATTR. Several new therapies aimed at the reduction, patients with ATTRwt treated with diflunisal, the
stabilization, or degradation of TTR have emerged levels of serum TTR were higher and the cTnI levels
recently (22). Cardiac biomarkers, mainly NT-proBNP, remained stable after 2 years of therapy compared to
along with imaging and clinical symptoms have been those in 23 untreated patients (14).
used in clinical trials in an effort to quantify the impact The efficacy of tafamidis, 20 mg once daily, in
of a few of these new therapies on cardiac function. treating amyloid cardiomyopathy was assessed by
TTR protein stabilizers, such as diflunisal, tafami- using cardiac biomarkers in 2 small, single-arm clinic
dis, and AG-10, are medications directed at the trials, both of which were published in 2015. The first of
stabilization of the TTR tetramer (2). Three small, those studies (25) presented post hoc analysis of an
single-arm clinical trials have searched for evidence of open-label study that monitored cardiac parameters in
the efficacy of diflunisal, 250 mg twice daily, in ATTR 21 patients with ATTRm (excluding p.Val50Met
cardiac amyloidosis using cardiac biomarkers. The first [V30M] and V122I mutations). That study did not
of those studies, published in 2012 (23) analyzed BNP demonstrate any significant change in NT-proBNP
8 Pregenzer-Wenzler et al. JACC: HEART FAILURE VOL. -, NO. -, 2020
Biomarkers in Amyloidosis - 2020:-–-

over the course of 12 months of treatment in patients hypothesized to act synergistically to reduce deposi-
presenting with either elevated or normal NT-proBNP tion of TTR and degrade the TTR amyloid matrix
levels. cTnI remained stable over the course of the already deposited in tissues. The first clinical trial to
study (25). The second study (26) included both pa- assess the efficacy of this class of therapy on ATTR
tients with ATTRwt and those with ATTRm with the cardiac amyloidosis was a small, phase II, open-label
V122I mutation. However, the results were only re- study using doxycycline and tauroursodeoxycholic
ported for the 31 patients with ATTRwt. There was a acid (TUDCA) (31). Only 7 patients completed the full
nonsignificant elevation in NT-proBNP and an average 12 months, and all of those patients had evidence of
increase in cTnT/I in that population after 12 months of cardiac involvement at baseline. NT-proBNP levels
treatment with tafamidis. In the absence of a control increased in 3 patients and remained stable in 4, and
group, biomarker results were compared to those re- no patients exhibited clinical evidence of cardiac
ported for the patients with ATTRwt in the TRACS progression (31). Another phase II study (32) pub-
(Transthyretin Amyloidosis Cardiac Study) observa- lished in 2017 evaluated the combination of doxycy-
tional cohort (27), which had demonstrated a larger, cline and ursodeoxycholic acid (UDCA) in patients
increase in NT-proBNP over a similar time period and with known ATTR cardiac amyloidosis; however, in
indicated that tafamidis was able to slow progression that study, doxycycline was intermittently dis-
of cardiac disease (26). Recently, the results of the first continued for periods of 2 weeks after every 4 weeks
phase III study of tafamidis (ATTR-ACT [Tafamidis in of treatment. Only 14% of the initial 28 patients
Transthyretin Cardiomyopathy Clinical Trial]) were completed the study. NT-proBNP levels remained
published. The multicenter trial randomized 264 pa- stable for the first 6 months but rose significantly at 1
tients with ATTR amyloidosis (wild-type and mutant) year. Participation in the study was terminated early
to receive either 80 mg of tafamidis, 20 mg of tafami- for 14% of patients due to treatment failure, which
dis, or placebo in ratio of 2:1:2 for 30 months. Tafamidis was defined as a 30% increase in NT-proBNP from
demonstrated a significant reduction in all-cause baseline (32).
mortality compared to placebo (29.5% vs. 42.9%) and Recent publications with TTR gene silencers have
a significant reduction of cardiovascular related hos- provided encouraging results for cardiac response to
pitalizations (0.48 per year vs. 0.70 per year, respec- therapy. The APOLLO study, published in 2018, ran-
tively). These outcomes were calculated using domized 225 patients with ATTRm and poly-
aggregate data for the 2 doses and prespecified anal- neuropathy to patisiran therapy, 0.3 mg/kg or placebo
ysis of 80 versus 20 mg showed similar benefits. In once every 3 weeks. That study demonstrated a sig-
relation to biomarkers, the study found that the pa- nificant improvement in neuropathy and quality of
tients who received tafamidis had lower elevations life; and in a subgroup of patients with cardiac
(least squares mean differences) in NT-proBNP than involvement, there was a decrease in the NT-proBNP-
those who received placebo at months 12 (735.14) and to-baseline ratio of 0.89 in the patisiran arm at
30 (2,180.54), suggesting a sustained biologic effect 18 months compared to 1.89 in the placebo group,
over time related to tafamidis (28). suggesting improved cardiac function (33). A subse-
AG-10 is a new TTR stabilizer that was tested in a quent publication focused on the outcomes in 126
phase II clinical trial in 49 patients with ATTR car- patients with cardiac involvement defined as patients
diomyopathy (wild type or mutant). Subjects were with left ventricular wall thickness $13 mm and no
randomized to receive 400 mg or 800 mg or placebo history of aortic valve disease or hypertension. In that
in 1:1:1 ratio. Subjects taking AG10 achieved more cardiac population, patients taking patisiran had a
than 90% stabilization of the tetrater with satisfac- 55% reduction in NT-proBNP at 18 months compared
tory safety and tolerability. The study measured to placebo (a fold-change patisiran-to-placebo ratio of
serum TTR levels (pre-albumin) as a surrogate 0.45; 95% confidence interval: 0.34 to 0.59; p ¼ 7.7 
endpoint for in vivo response to therapy. At day 28, 108 (34).
patients receiving 400 and 800 mg of AG-10 had
higher levels of 36% and 50% TTR, respectively; but NOVEL BIOMARKERS IN AL AND ATTR. At least 10
patients taking placebo experienced a reduction of 7% other novel biomarkers have been studied in patients
(29). Similar to the measurement of levels of diflu- with cardiac amyloidosis (Table 4). Of the biomarkers
nisal (14), serum levels of TTR have the potential to evaluated, preliminary studies suggest that von Wil-
become a cost-effective method to assess response to lebrand factor (35), mid-regional pro-adrenomedullin
therapy in patients with ATTR amyloidosis (30). (36), growth differentiation factor-15 (37,38), osteo-
Amyloid degraders, such as the combination ther- pontin (39), soluble suppression of tumorigenicity 2
apy of doxycycline and secondary bile acids are (40), and osteoprotegerin (41) may be able to improve
JACC: HEART FAILURE VOL. -, NO. -, 2020 Pregenzer-Wenzler et al. 9
- 2020:-–- Biomarkers in Amyloidosis

prognostication in high-risk patients with AL cardiac Review of how cardiac biomarkers have been used
amyloidosis when substituted for or used in and studied in patients with cardiac amyloidosis re-
conjunction with the existing Mayo staging systems. veals the need for continued investigation in a num-
Preliminary studies also suggested that high- ber of areas. Further risk stratification of patients
sensitivity cardiac troponin T (hs-cTnT) had the po- with high-risk (Mayo Stages 3b and IV) AL cardiac
tential to improve the sensitivity of the Mayo staging amyloidosis is needed to direct and, if necessary, risk-
system (19,42). Although the most recent study did not adapt prompt therapeutic interventions. The addition
show that hs-cTnT was able to contribute additional of a higher NT-proBNP threshold or the use of a novel
prognostic information to the existing staging sys- cardiac biomarker to further refine the Mayo staging
tems, it did demonstrate its potential to simplify the system has been explored (19,36,37,39,41–43,50).
prognostic algorithm by replacing the combination of Furthermore, the effects of atrial fibrillation and renal
NT-proBNP and a cardiac troponin in the Mayo staging failure in the Mayo staging system require further
system (43). Additional areas of study in cardiac investigation. Additionally, new treatment options
amyloidosis using novel biomarkers include the eval- for ATTR underscore the need for further evaluation
uation of matrix metalloproteinases and tissue in- of how cardiac biomarkers reflect prognosis and dis-
hibitors of metalloproteinases to differentiate ease progression in ATTRwt and ATTRm cardiac
between AL and ATTR cardiac amyloidosis (44,45) and amyloidosis to determine whether these biomarkers
the use of both hs-cTnT (46) and hepatocyte growth are accurate indicators of treatment response.
factor (47) to differentiate between cardiac amyloid- Further delineation of how the natural history and
osis and other causes of cardiomyopathy (38). the differences between ATTRwt and ATTRm are
defined by cardiac biomarkers is necessary to better
CONCLUSION AND FUTURE PROSPECTS
understand the implication of post-treatment cardiac
biomarker levels (23–26,31,32). Finally, the recogni-
In AL cardiac amyloidosis, cardiac biomarkers have
tion of ATTR cardiac amyloidosis as an under-
been used successfully to develop staging systems that
diagnosed, treatable cause of diastolic heart failure,
have been consistently validated in predicting base-
the significant difference in treatment of AL and
line prognosis at time of diagnosis and have demon-
ATTR, and the rapidly progressive nature of AL car-
strated utility in predicting prognosis in response to
diac amyloidosis identify the need for simple,
treatment (6,7,48). In addition, NT-proBNP has been
noninvasive methods of differentiating AL and ATTR
successfully established and validated as a surrogate
cardiac amyloidosis from each other and from other
marker for survival in AL based on treatment response
causes of diastolic heart failure (44–46). As the diag-
(21,49). As advances in disease-modifying therapies
nosis and treatment of cardiac amyloidosis continue
continue to be developed and as ATTR cardiac
to evolve rapidly, the use of cardiac biomarkers in
amyloidosis has become an increasingly recognized
this progressive, fatal disease process remains
cause of diastolic dysfunction in our aging population,
an exciting, clinically relevant area of active
the need for methods of early accurate diagnosis, risk
investigation.
stratification, and assessment of therapeutic response
for cardiac amyloidosis will continue to grow. Cardiac
biomarkers provide a noninvasive, easily accessible, ADDRESS FOR CORRESPONDENCE: Dr. Jose Nativi-
relatively inexpensive method for evaluating cardiac Nicolau, Cardiac Amyloidosis Program, University
disease and its progression, and have the potential to of Utah School of Medicine, 50 North Medical
take on a more expansive role in the diagnosis and Drive, Salt Lake City, Utah 84132. E-mail: jose.
ongoing assessment of cardiac amyloidosis. [email protected].

REFERENCES

1. Merlini G, Bellotti V. Molecular mechanisms of raised serum cardiac troponins. Lancet 2003;361: systemic amyloidosis. J Clin Oncol 2004;22:
amyloidosis. N Engl J Med 2003;349:583–96. 1787–9. 3751–7.
2. Patel KS, Hawkins PN. Cardiac amyloidosis: 5. Palladini G, Campana C, Klersy C, et al. 7. Kumar S, Dispenzieri A, Lacy MQ, et al.
where are we today? J Intern Med 2015;278: Serum N-terminal pro-brain natriuretic pep- Revised prognostic staging system for
126–44. tide is a sensitive marker of myocardial light chain amyloidosis incorporating cardiac
3. Jaffe AS, Ravkilde J, Roberts R, et al. It’s time dysfunction in AL amyloidosis. Circulation biomarkers and serum free light
for a change to a troponin standard. Circulation 2003;107:2440–5. chain measurements. J Clin Oncol 2012;30:
2000;102:1216–20. 989–95.
6. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum
4. Dispenzieri A, Kyle RA, Gertz MA, et al. Survival cardiac troponins and N-terminal pro-brain 8. Kumar SK, Gertz MA, Dispenzieri A. Validation
in patients with primary systemic amyloidosis and natriuretic peptide: a staging system for primary of Mayo Clinic staging system for light chain
10 Pregenzer-Wenzler et al. JACC: HEART FAILURE VOL. -, NO. -, 2020
Biomarkers in Amyloidosis - 2020:-–-

amyloidosis with high-sensitivity troponin. J Clin 23. Castano A, Helmke S, Alvarez J, Delisle S, 38. Kastritis E, Papassotiriou I, Merlini G, et al.
Oncol 2019;37:171–3. Maurer MS. Diflunisal for ATTR cardiac amyloid- Growth differentiation factor-15 is a new
osis. Congest Heart Fail 2012;18:315–9. biomarker for survival and renal outcomes in light
9. Wechalekar AD, Schonland SO, Kastritis E, et al.
chain amyloidosis. Blood 2018;131:1568–75.
A European collaborative study of treatment 24. Sekijima Y, Tojo K, Morita H, Koyama J,
outcomes in 346 patients with cardiac stage III AL Ikeda S. Safety and efficacy of long–term diflunisal 39. Kristen AV, Rosenberg M, Lindenmaier D, et al.
amyloidosis. Blood 2013;121:3420–7. administration in hereditary transthyretin (ATTR) Osteopontin: a novel predictor of survival in pa-
amyloidosis. Amyloid 2015;22:79–83. tients with systemic light-chain amyloidosis. Am-
10. Palladini G, Foli A, Milani P, et al. Best use of
yloid 2014;21:202–10.
cardiac biomarkers in patients with AL amyloidosis 25. Damy T, Judge DP, Kristen AV, Berthet K, Li H,
and renal failure. Am J Hematol 2012;87:465–71. Aarts J. Cardiac findings and events observed in an 40. Dispenzieri A, Gertz MA, Saenger A, et al.
open-label clinical trial of tafamidis in patients Soluble suppression of tumorigenicity 2 (sST2),
11. Dittrich T, Benner A, Kimmich C, et al. Perfor-
with non-Val30Met and non-Val122Ile hereditary but not galactin-3, adds to prognostication in
mance analysis of AL amyloidosis cardiac
transthyretin amyloidosis. J Cardiovasc Transl Res patients with systemic AL amyloidosis indepen-
biomarker staging systems with special focus on
2015;8:117–27. dent of NT-proBNP and troponin T. Am J Hematol
renal failure and atrial arrhythmia. Haematologica
26. Maurer MS, Grogan DR, Judge DP, et al. 2015;90:524–8.
2019;104:1451–9.
Tafamidis in transthyretin amyloid cardiomyopa- 41. Kastritis E, Gavriatopoulou M, Dimopoulos MA,
12. Grogan M, Scott CG, Kyle RA, et al. Natural
thy: effects on transthyretin stabilization and et al. Osteoprotegerin is a significant prognostic
history of wild–type transthyretin cardiac
clinical outcomes. Circ Heart Fail 2015;8:519–26. factor for overall survival in patients with primary
amyloidosis and risk stratification using a novel
27. Ruberg FL, Maurer MS, Judge DP, et al. Pro- systemic amyloidosis independent of the Mayo
staging system. J Am Coll Cardiol 2016;68:
spective evaluation of the morbidity and mortality staging. Blood Cancer J 2015;5:e319.
1014–20.
of wild-type and V122I mutant transthyretin am- 42. Kristen AV, Giannitsis E, Lehrke S, et al.
13. Gillmore JD, Damy T, Fontana M, et al. A new yloid cardiomyopathy: the Transthyretin Assessment of disease severity and outcome in
staging system for cardiac transthyretin amyloid- Amyloidosis Cardiac Study (TRACS). Am Heart J patients with systemic light-chain amyloidosis by
osis. Eur Heart J 2017;39:2799–806. 2012;164:222–8. the high-sensitivity troponin T assay. Blood 2010;
14. Hanson JLS, Arvanitis M, Koch CM, et al. Use of 28. Maurer MS, Schwartz JH, Gundapaneni B, et al. 116:2455–61.
serum transthyretin as a prognostic indicator and Tafamidis treatment for patients with trans- 43. Dispenzieri A, Gertz MA, Kumar SK, et al. High
predictor of outcome in cardiac amyloid disease thyretin amyloid cardiomyopathy. N Engl J Med sensitivity cardiac troponin T in patients with
associated with wild-type transthyretin. Circ Heart 2018;379:1007–16. immunoglobulin light chain amyloidosis. Heart
Fail 2018;11:e004000.
29. Judge DP, Heitner SB, Falk RH, et al. Trans- 2014;100:383–8.
15. Apple FS, Ler R, Murakami MM. Determination thyretin stabilization by AG10 in symptomatic 44. Biolo A, Ramamurthy S, Connors LH, et al.
of 19 cardiac troponin I and T assay 99th percen- transthyretin amyloid cardiomyopathy. J Am Coll Matrix metalloproteinases and their tissue in-
tile values from a common presumably healthy Cardiol 2019;74:285–95. hibitors in cardiac amyloidosis: relationship to
population. Clin Chem 2012;58:1574–81. structural, functional myocardial changes and to
30. Nativi-Nicolau J. Serum transthyretin: predic-
16. Comenzo RL, Reece D, Palladini G, et al. tor of amyloidosis outcomes? Circ Heart Fail 2018; light chain amyloid deposition. Circ Heart Fail
Consensus guidelines for the conduct and report- 11:e004802. 2008;1:249–57.
ing of clinical trials in systemic light-chain 45. Tanaka K, Essick EE, Doros G, et al. Circulating
31. Obici L, Cortese A, Lozza A, et al. Doxycycline
amyloidosis. Leukemia 2012;26:2317–25. matrix metalloproteinases and tissue inhibitors of
plus tauroursodeoxycholic acid for transthyretin
17. Merlini G, Lousada I, Ando Y, et al. Rationale, amyloidosis: a phase II study. Amyloid 2012;19 metalloproteinases in cardiac amyloidosis. J Am
application and clinical qualification for Suppl 1:34–6. Heart Assoc 2013;2:e005868.
NT-proBNP as a surrogate end point in pivotal 46. Takashio S, Yamamuro M, Izumiya Y, et al.
32. Wixner J, Pilebro B, Lundgren HE, Olsson M,
clinical trials in patients with AL amyloidosis. Diagnostic utility of cardiac troponin T level in
Anan I. Effect of doxycycline and ursodeoxycholic
Leukemia 2016;30:1979–86. patients with cardiac amyloidosis. ESC Heart Fail
acid on transthyretin amyloidosis. Amyloid 2017;
18. Palladini G, Lavatelli F, Russo P, et al. Circu- 24:78–9. 2017;5:27–35.
lating amyloidogenic free light chains and serum 33. Adams D, Gonzalez-Duarte A, O’Riordan WD, 47. Swiger KJ, Friedman EA, Brittain EL, et al.
N-terminal natriuretic peptide type B decrease et al. Patisiran, an RNAi therapeutic, for hereditary Plasma hepatocyte growth factor is a novel marker
simultaneously in association with improvement of transthyretin amyloidosis. N Engl J Med 2018;379: of AL cardiac amyloidosis. Amyloid 2016;23:
survival in AL. Blood 2006;107:3854–8. 11–21. 242–8.
19. Palladini G, Barassi A, Klersy C, et al. The 34. Scott D, Solomon DA, Arnt K, et al. Effects of 48. Dispenzieri A, Gertz MA, Kyle RA, et al.
combination of high-sensitivity cardiac troponin T patisiran, an RNA interference therapeutic, on Prognostication of survival using cardiac troponins
(hs-cTnT) at presentation and changes in N-ter- cardiac parameters in patients with hereditary and N-terminal pro-brain natriuretic peptide in
minal natriuretic peptide type B (NT-proBNP) after transthyretin-mediated amyloidosis: an analysis of patients with primary systemic amyloidosis un-
chemotherapy best predicts survival in AL the APOLLO study. Circulation 2018;139:431–43. dergoing peripheral blood stem cell trans-
amyloidosis. Blood 2010;116:3426–30. plantation. Blood 2004;104:1881–7.
35. Kastritis E, Papassotiriou I, Terpos E, et al.
20. Kastritis E, Wechalekar AD, Dimopoulos MA, Clinical and prognostic significance of serum levels 49. Gertz MA, Landau HJ, Weiss BM. Organ
et al. Bortezomib with or without dexamethasone of von Willebrand factor and ADAMTS-13 antigens response in patients with AL amyloidosis treated
in primary systemic (light chain) amyloidosis. in AL amyloidosis. Blood 2016;128:405–9. with NEOD001, an amyloid–directed monoclonal
J Clin Oncol 2010;28:1031–7. antibody. Am J Hematol 2016;91:E506–8.
36. Palladini G, Barassi A, Perlini S, et al. Midre-
21. Palladini G, Dispenzieri A, Gertz MA, et al. New gional proadrenomedullin (MR-proADM) is a 50. Kristen AV, Biener M, Hegenbart U, et al.
criteria for response to treatment in immuno- powerful predictor of early death in AL amyloid- Evaluation of the clinical use of midregional
globulin light chain amyloidosis based on free osis. Amyloid 2011;18:216–21. pro-atrial natriuretic peptide (MR-proANP) in
light chain measurement and cardiac biomarkers: comparison to N-terminal pro-B-type natriuretic
37. Kastritis E, Papassotiriou I, Terpos E, et al.
impact on survival outcomes. J Clin Oncol 2012; peptide (NT-proBNP) for risk stratification in pa-
Growth differentiation factor-15 in patients with
30:4541–9. tients with light-chain amyloidosis. Int J Cardiol
light chain (AL) amyloidosis has independent
2014;176:1113–5.
22. Dubrey S, Ackermann E, Gillmore J. The prognostic significance and adds prognostic in-
transthyretin amyloidoses: advances in therapy. formation related to risk of early death and renal 51. Pinney JH, Whelan CJ, Petrie A, et al. Senile
Postgrad Med J 2015;91:439–48. outcomes. Blood 2014;124. systemic amyloidosis: clinical features at
JACC: HEART FAILURE VOL. -, NO. -, 2020 Pregenzer-Wenzler et al. 11
- 2020:-–- Biomarkers in Amyloidosis

presentation and outcome. J Am Heart Assoc disease associated with wild-type transthyretin: a 56. Kristen AV, Maurer MS, Rapezzi C, et al. Impact
2013;2:e000098. prospective, observational cohort study. Circula- of genotype and phenotype on cardiac biomarkers in
tion 2016;133:282–90. patients with transthyretin amyloidosis—report from
52. Kastritis E, Roussou M, Gavriatopoulou M,
the Transthyretin Amyloidosis Outcome Survey
et al. Long-term outcomes of primary sys- 54. Damy T, Jaccard A, Guellich A, et al. Identifi-
(THAOS). PLoS One 2017;12:e0173086.
temic light chain (AL) amyloidosis in cation of prognostic markers in transthyretin and
patients treated upfront with bortezomib or AL cardiac amyloidosis. Amyloid 2016;23: 57. Siepen FAD, Bauer R, Voss A, et al. Predictors of
lenalidomide and the importance of risk 194–202. survival stratification in patients with wild-type car-
adapted strategies. Am J Hematol 2015;90: diac amyloidosis. Clin Res Cardiol 2017;107:158–69.
55. Perfetto F, Bergesio F, Grifoni E, et al.
E60–5.
Different NT-proBNP circulating levels for
53. Connors LH, Sam F, Skinner M, et al. Heart different types of cardiac amyloidosis. KEY WORDS amyloidosis, biomarkers, light
failure resulting from age-related cardiac amyloid J Cardiovasc Med 2016;17:810–7. chains, transthyretin