Current Heart Failure Reports

https://doi.org/10.1007/s11897-020-00457-z

BIOMARKERS OF HEART FAILURE (WH TANG & J GRODIN, SECTION EDITOR)

Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis

Nicholas S. Hendren 1 & Lori R. Roth 1 & Justin L. Grodin 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Transthyretin amyloidosis is an increasingly recognized cause of restrictive cardiomyopathy related to
amyloid fibril deposition in cardiac tissues. As treatment therapies have emerged for transthyretin amyloidosis (ATTR), so has
interest in using biomarkers to identify disease prior to advanced presentation.
Recent Findings Lower levels of transthyretin and retinol binding protein-4 have been demonstrated in patients with pathogenic
mutations of transthyretin either with or without clinical disease. Levels associate with the severity of mutations as well as
response to treatment with transthyretin stabilizers or small interfering RNA molecules which silence transthyretin production.
Transthyretin stability is the rate limiting step of amyloid fibril formation and directly measuring transthyretin kinetic stability has
the potential to identify patients as risk as well as therapeutic response to treatment regardless of pathogenic or wild-type genetics.
In addition, non-antibody protein-based peptide probes have been developed that directedly measure misfolded transthyretin
oligomers due to transthyretin breakdown. Although promising, both TTR kinetic and protein peptide probes remain in early
stages of clinical investigation.
Summary Transthyretin, retinol binding protein-4, transthyretin kinetic stability, and protein-based peptide probes have potential
as biomarkers to facilitate an earlier ATTR diagnosis for patients with pathogenic transthyretin mutations.

Keywords Transthyretin amyloidosis . Retinol binding protein . Biomarkers

Introduction manifestations of ATTR [1]. Cardiac manifestations include

Cardiac transthyretin amyloidosis (ATTR) is a chronic, progres-
sive, and often fatal disease due to insoluble transthyretin (TTR)
protein deposition in organ systems throughout the body in
older adults (Fig. 1). These misfolded amyloid fibrils principal-
ly occur due to unstable TTR tetramers that can spontaneously
occur without a pathogenic mutation (wild-type transthyretin
amyloidosis, ATTRwt) or due to a pathogenic mutation that
increases TTR structural instability (hereditary transthyretin
amyloidosis, hATTR). Although a spectrum of symptoms can
be present, they are often related to cardiac and neurologic
This article is part of the Topical Collection on Biomarkers of Heart Failure
* Justin L. Grodin
Justin.Grodin@utsouthwestern.edu
Nicholas S. Hendren
nicholas.hendren@phhs.org
1
Division of Cardiology, Department of Internal Medicine, University
of Texas Southwestern Medical Center, Dallas, TX, USA
diastolic filling abnormalities, conduction system abnormali-
ties, arrhythmias, and heart failure [2]. Neurologic involvement
from ATTR is a source of substantial morbidity and is charac-
terized by sensory motor neuropathy, autonomic neuropathy,
and dysautonomia [3]. These symptoms can lead to a substan-
tial reduction in quality of life, worsening functional capacity,
and increased healthcare utilization [4–7].
The diagnosis of ATTR is typically delayed years after
initiation of symptoms. In a review of 534 patients with
ATTR, patients presented to the hospital a median of 17
[9–27] times with 3 [1–5] in-patient admissions in the
3 years preceding diagnosis [7]. Historically, median sur-
vival at the time of diagnosis has been estimated at approx-
imately 4.8 years for ATTRwt, 2.5 years with V122I
hATTR and about 5.8 years for non-V122I hATTR [7].
Fortunately, recent therapeutic advances have led to the
development of two major therapeutic drug classes with
the capacity to slow and halt ATTR disease progression.
TTR stabilizers bind to TTR stabilizing the protein com-
plex and reduce protein disassembly that leads to amyloid
deposition. The second class includes gene silencing

Fig. 1 Conceptual model of cardiac ATTR progression over time.
Changes in various parameters are shown. The relative scale specific to
each factor and time course are not proportional. Myocardial amyloid
infiltration occurs before clinically manifest changes in ejection
fraction, cardiac biomarkers, and renal function. Thus, most patients
with cardiac ATTR likely have a long latency period before declines in
functional capacity, which can occur rapidly in the context of multiple
hospitalizations for acute decompensated heart failure and arrhythmias.
The ideal emerging therapeutic window for novel therapies is
hypothesized to be before significant organ dysfunction has occurred
and before rapid and potentially irreversible declines in functional
therapies that silence hepatic production of TTR and dra-
matically reduce amyloid fibril formation [4, 8••, 9].
With the development of new therapies, screening strate-
gies to detect subclinical ATTR in the presymptomatic patient
have gained interest. Previously factors such as N-terminal
pro-B-type natriuretic peptide (NT-proBNP), left ventricular
ejection fraction, uric acid, troponin T, troponin I, and renal
function have been associated with survival but lack precision
to differentiate ATTR from alternative diseases [10–12].
Consequently, identifying prognostic, cost-effective, and eas-
ily applicable preclinical markers to screen large populations
at risk is crucial for early identification of patients with pre-
clinical ATTR that would benefit from treatment (Fig. 1).
Biomarkers are well suited to identify patients early in the
disease course. Biomarkers play a major role in the diagnosis,
risk stratification, and therapeutic decisions for many diseases
Curr Heart Fail Rep
capacity. *Biomarker Stage defined by the Mayo Clinic for ATTRwt as
cardiac troponin T (< 0.05 ng/mL) and amino-terminal pro-B-type
natriuretic peptide (< 3000 pg/mL) with stages I, II, and III defined as
having both, one, or neither of the markers below the threshold. ATTR
indicates transthyretin amyloidosis; hATTR, hereditary transthyretin
amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; KCCQ,
Kansas City Cardiomyopathy Questionnaire; 6 MWD, 6-min walk
distance; NYHA, New York Heart Association; QOL, quality of life.
Figure and caption used with permission from: Grodin JL, Maurer MS.
The Truth Is Unfolding About Transthyretin Cardiac Amyloidosis.
Circulation. 2019;140 (1):27–30
including heart failure; however, less is known about bio-
markers for ATTR. Currently transthyretin, retinol-binding
protein-4 (RBP4), measurements of TTR kinetic stability,
and non-antibody peptide probes have shown promise as po-
tential biomarkers to identify patients are risk for ATTR. As
such, we will review possible biomarkers and the evidence for
their utility.
Transthyretin
Commonly known as prealbumin, TTR is a liver-secreted
plasma protein composed of 4 identical 127-amino acid
monomers that are non-covalently bound and circulate as a
tetramer [13]. TTR functions as a carrier of thyroxine and its
binding partner to retinol-binding protein 4 (RBP4) [13].
Curr Heart Fail Rep
ATTR pathogenesis occurs when the TTR tetramer disassem-
bles into monomers which can then form amyloid fibrils
(Fig. 2).
TTR is a promising biomarker for ATTR for several rea-
sons. First, TTR has a short half-life allowing for serial mea-
surement, abnormal levels may predate clinical symptoms and
TTR levels are associated with survival in ATTR [13].
Second, the principal pathogenesis is an unstable TTR tetra-
mer leading to amyloid production. It has been observed that
patients with more pathogenic (destabilizing) mutations have
lower levels of TTR [13], while patients with TTR stabilizing
mutations have higher levels of TTR [14]. Lastly, treatment
with TTR stabilizers increases serum TTR levels and may
indicate a positive prognostic response to therapy [13].
Alternately, therapies that silence TTR translation led to dra-
matic reductions of serum TTR levels serving as a different
marker of therapeutic efficacy [4, 9].
TTR can be detected in fetal blood within 8 weeks of con-
ception and increases to approximately half the adult level in
healthy neonates [12]. At the onset of puberty, TTR levels
increase to adult levels with slightly higher levels in males
compared with females presumably due to higher levels of
testosterone (32.3 ± 4.9 mg/dL vs 28.3 ± 4.3 mg/dL) [15].
After age 50, TTR levels begin to progressively decline with
age and sex specific differences are eliminated during the sev-
enth decade of life [15]. As such, although there are sex-
specific differences that attenuate with age, they are modest
and typically do not overlap with frankly abnormal values.
Fig. 2 Pathobiology of transthyretin amyloid. The mechanism of
transthyretin (TTR) protein dissociation, misfolding, and aggregation as
amyloid fibrils is illustrated with resultant end-organ dysfunction. ATTR,
transthyretin amyloid; mRNA, messenger RNA. Figure and caption used
Transthyretin is a negative acute-phase reactant which re-
sults in lower levels during malnutrition or chronic inflamma-
tion [16, 17]. TTR is unusually rich in the amino acid tyrosine
which makes TTR more sensitive to protein deficient diets or
catabolic states [17]. Although it was previously used a nutri-
tional biomarker, the use of TTR to assess nutritional status is
no longer recommended as levels of TTR can be affected by
extreme zinc deficiency, calorie deficiencies or acute and/or
chronic inflammation in an unpredictable manner that is inde-
pendent of nutritional status [18]. Lastly, higher levels of TTR
are observed with glucocorticoid use, and acute liver injury
due to release from damaged hepatic cells [17].
A normal TTR concentration is 18–45 mg/dL which is
dependent on age, sex, and race [12] with a biological half-
life of about 2 days [17]. Multiple commercial labs have avail-
able testing to precisely quantify TTR; however, modest intra-
and inter-person variability occur can with serial measure-
ments. In a small study, serial TTR measurements were ob-
tained weekly for a month in 15 patients with biopsy proven
hATTR and 11 patients with a pathogenic mutation without
clinical ATTR [20]. The overall mean TTR value was
20.2 mg/dL with approximately 23% intrasubject variability
and 25% inter subject variability over 1 month [19].
Several studies have observed significantly lower levels of
TTR with inherited forms of ATTR amyloidosis [12]. For
many years, it has been observed that serum TTR concentra-
tions are relatively low in carriers of autosomal dominant
amyloidogenic TTR mutations even before the signs and
with permission from: Ruberg FL, Grogan M, Hanna M, Kelly JW,
Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-
the-Art Review. J Am Coll Cardiol. 2019;73 (23):2872–91

symptoms of familial amyloid polyneuropathy (FAP) become
apparent [20]. Total serum TTR concentrations were obtained
in 47 Swedish patients with varied states of clinical disease
known to be V30M amyloidogenic allele carriers. TTR levels
were significantly lower in V30M allele carriers compared
with homozygous wild-type individuals (16.8 vs. 22.0 mg/
dL, P = 0.005) [20]. Asymptomatic allele carriers were also
found to have an abnormal TTR level (19.3 mg/dL) [20]. This
observation was similarly reported in V30M carriers in pa-
tients of Portuguese, African, and Japanese ethnicity
supporting that asymptomatic carriers of pathogenic TTR mu-
tations may have abnormal TTR levels [20].
In a second, larger observational study in the US serum
TTR concentrations were also evaluated in a selected cohort
of patients older than 60 years. Forty-three patients with
biopsy-proven ATTRwt were compared with 128 Caucasian
control patients. Although TTR was slightly numerically
higher in control patients, there was no statistically significant
difference (24.8 vs 25.0 mg/dL; P = 0.72) [21]. There was also
no statistical difference between in TTR levels between all
patients with ATTRwt (N = 45) or controls (N = 128) com-
pared with 20 patients with light chain amyloidosis with heart
failure (237 vs 250 vs 195 mg/dL; P = 0.59, P = 0.24 respec-
tively) [21]. TTR levels were then evaluated in 828 Caucasian
and 826 African-American control patients. TTR levels were
each independently higher in men, patients younger than 60,
and Caucasians compared with African-Americans (26.3 vs
24.8 mg/dL) [21]. Finally, they identified 12 African-
American patients with a pathogenic V122I mutation. After
adjusting for age and sex, TTR levels were lower in patients
with a pathogenic mutation (17.1 vs 22.9 mg/dL). This study
supports a few important observations. First, TTR levels may
not differ enough between patients with ATTRwt and healthy
controls to serve as a precise biomarker for preclinical
ATTRwt. Second, in a small sample size TTR levels were
similar between patients with AL and control patients despite
concerns about AL confounding TTR levels. Finally, lower
TTR levels in a small selected cohort are supportive that TTR
should be investigated as a possible biomarker for hATTR.
Importantly, the V122I carriers had significantly lower serum
TTR concentrations despite the majority of subjects below the
age of clinical risk for ATTR [21].
Hanson et al. retrospectively evaluated 116 patients with
clinical ATTRwt compared with 30 control patients ≥ 60 years
old to evaluate TTR levels [12]. Baseline TTR levels were
prognostic and patients with baseline TTR ≥ 18 mg/dL had a
median survival time of 4.1 years versus 2.8 years in the group
with TTR < 18 mg/dL (P = 0.03, HR = 2.3, 95% CI 1.2–4.3)
[12]. Higher TTR values in both univariable and multivariable
analyses were positively associated with longer survival in
patients with ATTRwt [12]. As such, a serum TTR < 18 mg/
dL may have the potential to identify patients at increased risk
for clinical outcomes and associate with prognosis for
Curr Heart Fail Rep
established clinical ATTRwt; however, TTR may not be able
to discriminate preclinical ATTRwt from healthy subjects at
the population level [12]. Additional follow-up was complet-
ed in 23 untreated ATTRwt patients and 12 patients treated
with a TTR stabilizer. In the treated group, TTR increased at
year 1 and remained significant higher in the treated cohort at
2-year follow-up (20 vs. 31 mg/dL, P < 0.001) [12]. This is
one early observation that increases in TTR levels may also be
associated with a positive response to treatment.
In general, the more destabilizing the TTR mutation, the
more penetrant and severe the phenotype [22]. A super-
stabilizing mutation (T119M) has been identified that protects
carriers from clinical ATTR or FAP by reducing the dissociation
rate of TTR by over 33-fold compared with wild-type protein
[22]. Compound heterozygotes carrying both T119M and the
V30M mutations develop few if any manifestations of ATTR
[23]. One large observational study of 68,602 patients prospec-
tively identified 321 heterozygotes with the T119M mutation
(0.47% prevalence) [24]. Compared with non-carriers, hetero-
zygotes for T119M had a mean TTR level of 18.3 mg/dL vs
15.7 mg/dL, (P = 0.007) which represented a 17% difference.
When adjusted for age and sex, a 20% difference remained
[24]. Again, a higher TTR level was prognostic as T119M
heterozygotes had a median of 5 more years of life expectancy
compared with non-carriers (P = 0.04) [24]. This study supports
the observation that higher TTR levels and increased kinetic
stability are associated with improved clinical outcomes.
Two main mechanisms of treatment have been developed
for ATTR which include TTR stabilizing compounds and
small interfering RNA molecules to silence TTR production.
TTR levels may have prognostic ability for treatment for each
drug class. Suhr et al. recruited 29 patients with biopsy proven
ATTRwt or hATTR for a phase II clinical trial of patisiran
(small interfering RNA) with four different dosing regimens
[25]. Baseline serum TTR concentrations were similar across
the four groups; however, more intensive treatment led to
greater reduction of TTR with mean reductions of approxi-
mately 80% and maximal reductions of 90% [25]. In the phase
III clinical trial of patisiran, patients had a sustained 81%
reduction of TTR with clinical improvement of neuropathy
and quality of life [4], indicative that TTR may serve as a
surrogate marker for clinical response to patisiran.
Patients treated with TTR stabilizers such as tafamidis or
diflunisal have been observed to have higher levels of TTR
compared with non-treated patients [25]. Tafamidis binds to
TTR, and stabilizes TTR to reduce dissociation of TTR, which
is a rate-limiting step in amyloid fibril formation. Tafamidis is
shown to reduce morbidity and mortality in subjects with
ATTR in a large placebo controlled clinical trial [8••]. In a
review of 31 patients with ATTR (25 ATTRwt and 6 hATTR)
treated with tafamidis, serum TTR levels were obtained pre and
post medication initiation [26•]. The mean serum TTR levels
prestabilize administration were 20.6 ± 5.6 mg/dL and were
Curr Heart Fail Rep
similar between ATTRwt and hATTR patients [26•]. With
tafamidis, TTR levels increased in from 18.5 ± 7.2 to 28 ±
7.4 mg/dL in hATTR subjects (increase of 37%; P = 0.046)
and 21.3 ± 4.8 to 29.9 ± 6.0 in ATTRwt (increase of 40%;
P < 0.0001) [26•]. These increases did not appear to differ be-
tween men and women. Overall, this study was suggestive that
increased TTR kinetic stability with tafamidis translates to in-
creased levels of TTR in subjects with clinical ATTR.
A second TTR stabilizer, AG10, was tested in a phase II
clinical trial in patients with ATTR (11 hATTR, 38 ATTRwt)
and New York Heart Association Class II-III symptoms [13].
AG10 is a potent TTR stabilizer that stabilizes TTR > 90% by
mimicking the T119M variant which forms a stabilizing bond
within the TTR tetramer. In this trial, participants were given a
placebo, 400 mg or 800 mg dose twice daily of AG10 for
28 days. The baseline median TTR level was 22.0 ± 5.4 mg/
dL [13]. AG10 was a highly effective TTR stabilizer provid-
ing > 90% stabilization to the TTR tetramer leading to a 36%
increase of TTR in the 400 mg group, 50% increase in the
800 mg group, and a 7% decline in the placebo group [13].
There was also a greater increase observed in the hATTR
compared with ATTRwt group suggesting that AG10 may
more effective in less stable tetramers. However, the magni-
tude of change in serum TTR was less than the magnitude of
change with tafamidis.
In sum, TTR is a reproducible, easily quantifiable protein
associated with clinical outcomes and abnormal in patients
with both clinical and preclinical ATTR. TTR levels associate
with the degree of TTR instability and increases in TTR levels
are associated with treatment efficacy.
Retinol-Binding Protein
Retinol is a hydrophobic compound that requires binding to
retinol binding protein 4 (RBP4) in order to secreted into the
blood stream and delivered to target organs [27]. Both un-
bound retinol and RBP4 are rapidly cleared from the blood-
stream largely via urinary excretion (retinol) or urinary metab-
olism (RBP4). Retinol-RBP4 complexes then bind to TTR
which stabilizes the tetramer preventing TTR disassembly,
amyloid aggregation, [28], and urinary losses of RBP4 and
retinol [29]. RBP4 is primarily produced in the liver with an
additional 20% production from adipose tissue [27], and it has
been observed that RBP4 levels and TTR levels are associat-
ed. In a phase II clinical trial of patisiran, the level of serum
TTR reduction was highly correlated with the reduction in
circulating level of RBP4 (r2 = 0.89, P < 10−15) and vitamin
A (r2 = 0.89, P < 10−15) [25]. Thus, lower levels of RBP4
appear to parallel serum TTR levels.
Destabilizing TTR mutations that cause TTR instability
also translate into fewer circulating RBP4-TTR complexes
and increased urinary excretion of RBP4. However, lower
RBP4 levels may also destabilize TTR leading towards
increased amyloid production [30]. In a small cohort of 47
patients with ATTRwt and 27 patients with hATTR V122I,
serum RBP4 concentration was lower compared with non-
amyloid controls (31.5 vs 49.4 μg/mL, P < .001), and the dif-
ference persisted after adjusting for several confounders [31•].
As expected, RBP4 and TTR levels were highly correlated
(Spearman rho = 0.75, P = 0.001) [31•]. For screening pur-
poses, a RBP4 level < 49.5 μg/mL achieved a high sensitivity,
but poor specificity in this exploratory analysis for patients
with hATTR V122I [31•]. This analysis in combination with
additional observations suggests RBP4 levels are associated
with pathogenic TTR mutations and may be a reasonably
sensitive biomarker to screen for ATTR and that warrants
further investigation within the general population.
In a second study, RBP4 levels were obtained in 25 patients
with biopsy proven V122I ATTR and compared with 50 pa-
tients older than 60 years. Serum RBP4 concentrations were
found to be significantly lower in patients with V122I ATTR
compared with patients without amyloidosis (31.5 vs.
49.4 μg/mL, P < 0.001) despite adjustment for age, sex, tro-
ponin level, nutritional status, and echocardiographic param-
eters [32]. As seen previously, RBP4 and TTR levels were
highly correlated (Spearman rho = 0.75, P < 0.001) [32]. In
this small cohort of patients with V122I ATTR, RBP4 at a
threshold of 43 μg/mL maximized the prognostic value with
a sensitivity of 62% (95% CI: 47–77%) and a specificity of
88% (95% CI 76–100%) [35]. For a higher sensitivity a
threshold of 50 μg/mL maximized sensitivity at 100% (95%
CI, 100–100%); however, the specificity declined to 38%
(95% CI, 23–51%) [32]. In short, RBP4 merits further inves-
tigation as a biomarker for ATTR in a larger and more patho-
logically diverse cohort.
Despite the presence of pathogenic mutations in TTR, the
age of onset for clinical disease has considerable variance
within families and can include asymptomatic carriers as old
as 95 years old [33]. This suggests that additional factors may
modify disease penetrance. Mutations in RBP4 which either
stabilize or destabilize the TTR-RBP4 complex may affect the
penetrance of either hATTR or ATTRwt. In a review of 318
patients with a V30M mutation, genetic differences in RBP4
modified the age of onset for clinical symptoms of amyloid-
osis by as much as 19 years [30]. This is suggestive that RBP4
may have a pathophysiological link to ATTR which can serve
as protective role against pathological mutations and/or serve
as a marker of more pathological ATTR mutations to influence
the disease penetrance of ATTR. In sum, RBP4 levels are
associated with pathogenic mutations and show promise as a
biomarker for ATTR in limited clinical cohorts.
Novel Marks of TTR Stability
The fundamental problem and rate-limiting step of ATTR re-
lates to the disassembly of unstable TTR complexes into

amyloid fibrils. Two methods currently being evaluated as a
biomarker for ATTR include measuring kinetic stability of the
TTR homotetramer and using peptide probes to quantify the
level of misfolded TTR oligomers. One established method to
quantify the stability of TTR tetramers involves measuring the
rate of subunit exchange with the TTR tetramer. The rate of
exchange is referred to as kinetic stability and may serve as a
surrogate biomarker for the prediction of the clinical outcome
and response to therapy [34].
The variability in the age of onset or the aggressiveness of
the hereditary TTR amyloidosis can, in part, be attributed to
differences in the thermodynamic and kinetic stability of tet-
ramers comprising disease-associated and ATTRwt subunits
[34]. The decreased kinetic stability of TTR tetramers incor-
porating pathogenic mutated subunits leads to an increased
rate of TTR dissociation [34]. Pharmacologic therapies that
stabilize TTR by binding to the native TTR tetramer slow
the progression of disease by limiting TTR disassembly.
This is illustrated by tafamidis which stabilizes TTR 4-fold
in patients receiving the drug and reduces the progression of
symptoms [34].
TTR kinetics may also be able to quantify a patient’s re-
sponse to kinetic stabilizer treatment, which is especially valu-
able for patients carrying substantially destabilized, rare, or
currently uncharacterized TTR mutations. With future study,
the quantification of TTR kinetic stability has the potential to
become a surrogate biomarker to predict clinical response to
therapies or screen for asymptomatic patients at risk for
ATTRwt or hATTR [34].
A second novel diagnostic tool is the development of pep-
tide probes that selectively bind to pathogenic TTR oligomers
in the serum of patients with hATTR. These probes work by
binding to specific peptide sequences in misfolded TTR olig-
omers which are not available in the more densely bound
native TTR or TTR amyloid fibrils [35]. This allows the
probes to precisely quantitate the level of TTR oligomers sep-
arate from amyloid fibrils or TTR regardless of the genetic
mutations in TTR or RBP4 [35]. In small highly selected
cohorts, peptide probes identified higher levels of misfolded
TTR oligomers in patients with clinical FAP, but not in healthy
controls, asymptomatic carriers of mutations associated with
FAP, or patients with cardiac hATTR or ATTRwt [35].
Additional investigation in patients with FAP observed a sig-
nificant decrease in misfolded oligomers for patients treated
with tafamidis (1.8 fold decline) or liver transplantation (no
detectable pathogenic TTR oligomers) [35]. As such peptide
probes may be an evolving biomarker for FAP with levels
indicative of a response to therapy, but further investigation
will be required.
To date, both TTR kinetic stability and protein-based pep-
tide probes have had limited study in the clinical and preclin-
ical ATTR population. Both tests could be developed to screen
patients for pathogenic TTR prior to symptom development
Curr Heart Fail Rep
rather than expensive genotyping which may discover genetic
mutations of undetermined significance. Additionally, these
test results may associate with a response to disease modifying
therapy in future research studies. However, significant uncer-
tainly remains about the utility of both tests and it remains to
be seen if changes in TTR kinetics or oligomer concentration
associate with clinical outcomes.
Conclusion
In sum, ATTR is an increasingly recognized cause of heart
failure. With development of recent pharmacotherapies iden-
tifying patients earlier in the disease course to modifying dis-
ease sequalae has become an important area of investigation.
The identification of a biomarker to identify those at risk of or
diagnose patients with ATTR in a preclinical stage is a large
unmet need because many centers do not have the facilities or
expertise needed to complete cardiac magnetic resonance im-
aging or bone scintigraphy scans making them impractical at a
national level. Although earlier studies are promising, further
investigation is needed to clarify if abnormalities in TTR,
RBP4, TTR kinetic stability, and transthyretin oligomers can
precisely identify patients with preclinical ATTR that merit
further clinical evaluation.
Compliance with Ethical Standards
Conflict of Interest Dr. Grodin received research funding from the Texas
Health Resources Clinical Scholarship and receives consulting income
from Pfizer and Eidos Therapeutics. Dr. Nicholas Hendren and Lori Roth
declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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