A new staging system using right atrial strain in patients with immunoglobulin light‐chain cardiac amyloidosis

Abstract

Aims
There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with immunoglobulin light‐chain (AL) cardiac amyloidosis.

Methods and results
Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from 2007 to 2022, 72 patients with sufficient two‐dimensional speckle tracking imaging data without chemotherapy before the diagnosis were retrospectively analysed. During a median follow‐up of 403 days, 31 deaths occurred. Age and the rate of male sex were not significantly different between the all‐cause death group and the survival group (age, 70.4 ± 8.8 years vs. 67.0 ± 10.0 years, P = 0.14, male sex, 65% vs. 66%, P = 0.91). The estimated glomerular filtration rate (eGFR) was significantly lower, and B‐type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs‐cTnT) were significantly higher, in the all‐cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m² vs. 59.4 ± 24.4 mL/min/1.73 m², P < 0.05, BNP, 725 [360–1312] pg/mL vs. 123 [81–310] pg/mL, P < 0.01, hs‐cTnT, 0.12 [0.07–0.18] ng/mL vs. 0.05 [0.03–0.08] ng/mL, P < 0.01). Left ventricular (LV) global longitudinal strain (GLS) (LV‐GLS), left atrial strain during the reservoir phase (LASr), right ventricular GLS (RV‐GLS), and RASr were significantly lower in the all‐cause death group versus the survival group (LV‐GLS, 8.5 ± 4.3% vs. 11.8 ± 3.8%, P < 0.01, LASr, 8.8 ± 7.1% vs. 14.3 ± 8.1%, P < 0.01, RV‐GLS, 11.6 ± 5.1% vs. 16.4 ± 3.9%, P < 0.01, RASr, 10.2 ± 7.3% vs. 20.7 ± 9.5%, P < 0.01). RASr was significantly associated with all‐cause death after adjusting for RV‐GLS, LV‐GLS and LASr (hazard ratio [HR]: 0.91, 95% confidence interval [95% CI]: 0.83–0.99, P < 0.05). RASr and log‐transformed BNP were significantly associated with all‐cause death after adjusting for log‐transformed troponin T and eGFR (RASr, HR: 0.93, 95% CI: 0.87–1.00, P < 0.05; log‐transformed BNP, HR: 2.10, 95% CI: 1.17–3.79, P < 0.05). The optimal cut‐off values were RASr: 16.4% (sensitivity: 66%, specificity: 84%, area under curve [AUC]: 0.81) and BNP: 311.2 pg/mL (sensitivity: 83%, specificity: 78%, AUC: 0.82) to predict all‐cause mortality using ROC analysis. Kaplan–Meier analysis revealed that patients with low RASr (<16.4%) or high BNP (>311.2 pg/mL) had a significantly high probability of all‐cause death (both, P < 0.01). We devised a new staging score by adding 1 point if RASr decreased or BNP levels increased more than each cut‐off value. The HR for all‐cause death using score 0 as a reference was 5.95 (95% CI: 1.19–29.79; P < 0.05) for score 1 and 23.29 (95% CI: 5.37–100.98; P < 0.01) for score 2.

Conclusions
The new staging system using RASr and BNP predicted prognosis in patients with AL cardiac amyloidosis.

Full text

A new staging system using right atrial strain in
patients with immunoglobulin light-chain cardiac
amyloidosis
Hiroki Usuku
1,2,3
, Eiichiro Yamamoto
2,3
*, Daisuke Sueta
2,3
, Rumi Shinriki
1
, Fumi Oike
2,3
, Noriaki Tabata
2,3
,
Masanobu Ishii
2,3
, Shinsuke Hanatani
2,3
, Tadashi Hoshiyama
2,3
, Hisanori Kanazawa
2,3
, Yuichiro Arima
2,3
,
Seiji Takashio
2,3
, Yawara Kawano
4
, Seitaro Oda
5
, Hiroaki Kawano
2,3
, Mitsuharu Ueda
3,6
and Kenichi Tsujita
2,3
1
Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, Japan;
2
Department of Cardiovascular Medicine, Graduate School of Medical Sciences,
Kumamoto University, Kumamoto, Japan;
3
Center of Metabolic Regulation of Healthy Aging, Kumamoto University Faculty of Life Sciences, Kumamoto, Japan;
4
Department
of Hematology, Rheumatology, and Infectious Diseases, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan;
5
Department of Diagnostic Radiology,
Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; and
6
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto,
Japan
Abstract
Aims There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with
immunoglobulin light-chain (AL) cardiac amyloidosis.
Methods and results Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital
from 2007 to 2022, 72 patients with sufficient two-dimensional speckle tracking imaging data without chemotherapy before
the diagnosis were retrospectively analysed. During a median follow-up of 403 days, 31 deaths occurred. Age and the rate of
male sex were not significantly different between the all-cause death group and the survival group (age, 70.4 ± 8.8 years vs.
67.0 ± 10.0 years, P= 0.14, male sex, 65% vs. 66%, P= 0.91). The estimated glomerular filtration rate (eGFR) was significantly
lower, and B-type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs-cTnT) were significantly higher, in the
all-cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m
2
vs. 59.4 ± 24.4 mL/min/1.73 m
2
,
P<0.05, BNP, 725 [360–1312] pg/mL vs. 123 [81–310] pg/mL, P<0.01, hs-cTnT, 0.12 [0.07–0.18] ng/mL vs. 0.05 [0.03–
0.08] ng/mL, P<0.01). Left ventricular (LV) global longitudinal strain (GLS) (LV-GLS), left atrial strain during the reservoir
phase (LASr), right ventricular GLS (RV-GLS), and RASr were significantly lower in the all-cause death group versus the survival
group (LV-GLS, 8.5 ± 4.3% vs. 11.8 ± 3.8%, P<0.01, LASr, 8.8 ± 7.1% vs. 14.3 ± 8.1%, P<0.01, RV-GLS, 11.6 ± 5.1% vs.
16.4 ± 3.9%, P<0.01, RASr, 10.2 ± 7.3% vs. 20.7 ± 9.5%, P<0.01). RASr was significantly associated with all-cause death after
adjusting for RV-GLS, LV-GLS and LASr (hazard ratio [HR]: 0.91, 95% confidence interval [95% CI]: 0.83–0.99, P<0.05). RASr
and log-transformed BNP were significantly associated with all-cause death after adjusting for log-transformed troponin T and
eGFR (RASr, HR: 0.93, 95% CI: 0.87–1.00, P<0.05; log-transformed BNP, HR: 2.10, 95% CI: 1.17–3.79, P<0.05). The optimal
cut-off values were RASr: 16.4% (sensitivity: 66%, specificity: 84%, area under curve [AUC]: 0.81) and BNP: 311.2 pg/mL
(sensitivity: 83%, specificity: 78%, AUC: 0.82) to predict all-cause mortality using ROC analysis. Kaplan–Meier analysis revealed
that patients with low RASr (<16.4%) or high BNP (>311.2 pg/mL) had a significantly high probability of all-cause death (both,
P<0.01). We devised a new staging score by adding 1 point if RASr decreased or BNP levels increased more than each cut-off
value. The HR for all-cause death using score 0 as a reference was 5.95 (95% CI: 1.19–29.79; P<0.05) for score 1 and 23.29
(95% CI: 5.37–100.98; P<0.01) for score 2.
Conclusions The new staging system using RASr and BNP predicted prognosis in patients with AL cardiac amyloidosis.
Keywords B-type natriuretic peptide; Immunoglobulin light-chain cardiac amyloidosis; Right atrial strain during the reservoir phase
Received:
16
July
2023
; Revised:
9
January
2024
; Accepted:
21
January
2024
*Correspondence to: Eiichiro Yamamoto, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University,
1
-
1
-
1
Honjo, Chuo-ku,
Kumamoto
860
-
8556
, Japan. Email: eyamamo@kumamoto-u.ac.jp
ORIGINAL ARTICLE
© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me-
dium, provided the original work is properly cited and is not used for commercial purposes.
ESC HEART FAILURE
ESC Heart Failure 2024; 11: 1612–1624
Published online 23 February 2024 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.14710

Introduction
Immunoglobulin light-chain (AL) amyloidosis is a multisystem
disease caused by the deposition of amyloid fibrils in organ
tissues, and it arises from misfolded light chains most com-
monly produced by clonal expansion of monoclonal plasma
cells.
1
Cardiac involvement has been noted in approximately
70% of patients with AL amyloidosis
2,3
and is the primary
driver of death in these patients.
4
Myocardial amyloid deposition in cardiac tissues causes
dysfunction through both architectural damages and direct
myocardial toxicity and oxidative damage by amyloidogenic
light chains.
5
Survival staging using B-type natriuretic peptide
(BNP) and cardiac troponin can predict a poor prognosis in AL
amyloidosis.
6
Echocardiographic findings also provide diag-
nostic and prognostic information in patients with AL amy-
loidosis suspected of having cardiac involvement.
7,8
Two-dimensional strain analysis based on speckle-tracking
echocardiography has recently been used to detect myocar-
dial deformation. Global reduction of left ventricular (LV)
global longitudinal strain (GLS) (LV-GLS) is a significant prog-
nostic factor in cardiac amyloidosis.
9,10
Because cardiac amy-
loidosis is a diffuse disease that affects all four chambers,
11
we previously revealed the usefulness of left atrial longitudi-
nal strain (LALS) and right ventricular (RV) GLS (RV-GLS) to
predict cardiovascular events in wild-type transthyretin amy-
loid cardiomyopathy (ATTRwt-CM).
12,13
However, the useful-
ness of right atrial (RA) LS as a predictive factor in patients
with AL cardiac amyloidosis has not been sufficiently clarified.
Therefore, we investigated whether RALS estimated by two-
dimensional speckle-tracking echocardiography provides
prognostic information in patients with AL cardiac amyloid-
osis. We also evaluated a new staging system using
biomarkers and echocardiographic findings to predict the
prognosis of AL cardiac amyloidosis.
Methods
Study population
Seventy-eight patients were diagnosed with AL cardiac amy-
loidosis at Kumamoto University Hospital from January 2007
to December 2022. Of these patients, five were excluded be-
cause they had no transthoracic echocardiography data at di-
agnosis or had insufficient two-dimensional speckle-tracking
echocardiography data. An additional patient was excluded
because he received chemotherapy before the diagnosis of
cardiac amyloidosis. The remaining 72 patients diagnosed
with AL cardiac amyloidosis were enrolled in this study
(Figure
1
). Baseline clinical characteristics and echocardio-
graphic data at diagnosis were obtained while the patients
were clinically stable.
This study conformed to the principles outlined in the Dec-
laration of Helsinki and was approved by the institutional re-
view board and ethics committee of Kumamoto University
(No. 1588). The requirement to obtain informed consent
was waived because of the low-risk nature of this retrospec-
tive study regarding patient identification, and the inability to
obtain consent directly from all patients because many
patients were already dead. Instead, we announced this
study protocol extensively at Kumamoto University Hospital
and on our website (http://www2.kuh.kumamoto-u.ac.jp/
tyuokensabu/index.html) and gave patients the opportunity
to withdraw from the study.
Diagnosis of immunoglobulin light-chain cardiac
amyloidosis
The diagnosis of amyloid deposition was based on Congo
red staining and apple-green birefringence visualized with
Figure 1 Study flow chart detailing the inclusion and exclusion criteria for the study patients. AL cardiac amyloidosis, immunoglobulin light-chain car-
diac amyloidosis; TTE, transthoracic echocardiography.
RASr and BNP in AL amyloidosis 1613
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

cross-polarized light microscopy in biopsied tissue samples.
AL amyloidosis was diagnosed on the basis of positive stain-
ing for immunoglobulin light chains by immunohistochemical
staining. We diagnosed cardiac amyloidosis when amyloid de-
position was observed in the myocardium and typical findings
were observed on cardiac magnetic resonance imaging (e.g.
LV subendocardial late gadolinium enhancement or signifi-
cantly elevated native T1 and extracellular volume fraction
values). AL cardiac amyloidosis was also diagnosed by echo-
cardiography when a thickened LV wall (interventricular sep-
tal thickness at end-diastole (IVSTd) >12 mm) and +1 or 2
characteristic echo findings (grade ≥2 diastolic dysfunction;
reduced S′,e′and a′velocities (<5 cm/s); decreased GLS to
≥15%) or ECHO score ≥8 was observed in accordance
with 2022 European Society of Cardiology cardio-oncology
guidelines.
14
Previous survival staging system
In accordance with the survival staging system of Lilleness
et al.,
6
which uses BNP and cardiac troponin concentrations,
we separated the enrolled patients into four groups (stage
I, II, IIIa, and IIIb) using the following reported cut-off defini-
tions: stage I, both BNP and high-sensitivity cardiac troponin
T (hs-cTnT) lower than the cutoff points (BNP: 81 pg/mL,
hs-cTnT: 0.035 ng/mL); stage II: either BNP or hs-cTnT higher
than the cutoff point (BNP: 81 pg/mL, hs-cTnT: 0.035 ng/mL);
and stage III: both BNP and hs-cTnT higher than the cutoff
points (BNP: 81 pg/mL, hs-cTnT: 0.035 ng/mL). Patients in
stage III were further divided on the basis of the BNP
levels as stage IIIa (BNP ≤700 pg/mL) and stage IIIb
(BNP >700 pg/mL).
Conventional echocardiographic measurements
Transthoracic echocardiography was performed in patients
in a stable condition using the Vivid E95 or 7 (GE Vingmed
Ultrasound AS, Horten, Norway), Aplio 500 (Canon Medical
Systems Corp., Otawara, Tochigi, Japan), and Epiq 7G
(Philips Healthcare, Bothell, WA, USA), which were equipped
with a 2.5-MHz phased-array transducer. Conventional
echocardiography was performed in accordance with the
recommendations of the American Society of Echocardiogra-
phy (ASE) and the European Association of Cardiovascular
Imaging.
15,16
LV wall thickness was acquired in the
parasternal long-axis view. LV ejection fraction (LVEF) and
LA volume index were calculated using a modified Simpson’s
method. Peak early diastolic velocity of LV inflow (E veloc-
ity), late atrial diastolic velocity of LV inflow (A velocity),
and peak early diastolic velocity on the septal corner of
the mitral annulus (e′) were measured in the apical
four-chamber view. Moderate or severe valvular disease in
accordance with the ASE guideline
17
was defined as valvular
disease in this study. To minimize bias, the echocardiogra-
phy reviewers were blinded to the patients’clinical history
and data.
Two-dimensional speckle-tracking
echocardiography
Two-dimensional speckle-tracking echocardiography was
performed by one operator (first operator) who was
blinded to the clinical data and who differed from the oper-
ator who performed the conventional echocardiography.
Two-dimensional speckle-tracking echocardiography was
performed using cardiac performance analysis with a manual
vendor-independent measurement package (TomTec-Arena;
TomTec Imaging Systems, Unterschleissheim, Germany). To
assess LV strain, the LS, calculated from the echocardio-
graphic images in the four-, three-, and two-chamber views,
was determined in 16 segments of the LV in accordance with
the ASE guidelines.
15
LV-GLS was calculated as the average
LS of these 16 segments. To assess RV-GLS, we evaluated
the average value of the longitudinal peak systolic strain
from the free wall and the septal wall of the RV in the
RV-focused apical four-chamber view.
18
To assess LALS, the
regional strain was determined in three segments (septal,
roof, and lateral) obtained from echocardiographic images
in the four-chamber apical view in accordance with our pre-
vious report.
13,19
To assess RALS, the regional strain was de-
termined in three segments (septal, roof, and lateral) ob-
tained from echocardiographic images in the RV-focused
apical four-chamber view (Figure
2
). To evaluate LA and RA
strain components, the zero-strain reference was defined at
end-diastole. In the present study, we used LA strain during
the reservoir phase (LASr) and right atrial strain during the
reservoir phase (RASr) as indicators of LA and RA function,
respectively, because we previously revealed the prognostic
utility of LA reservoir function in cardiac amyloidosis.
13
Strains are described as absolute values. Intraobserver
variability was assessed as follows: the first operator
re-evaluated RASr measurements from 20 patients 1 month
after the initial calculation. Interobserver variability was
assessed as follows: the RASr measurements from 20 pa-
tients were paired with the measurements of another oper-
ator (second operator). The intraobserver and interobserver
variabilities were assessed using the intraclass correlation
coefficient (ICC). Analysis of the intraobserver and interob-
server variabilities showed good correlations for RASr
measurements [mean ICC: 0.96, 95% confidence interval
(CI): 0.90–0.98, and mean ICC: 0.97, 95% CI: 0.91–0.99,
respectively].
1614 H. Usuku et al.
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

Data collection
For patients who received chemotherapy, laboratory exami-
nation and transthoracic echocardiography were performed
before starting chemotherapy. Mortality was identified by a
search of the patients’medical records and confirmed by a
questionnaire and direct contact via a telephone interview
with the patient or, if deceased, a family member. These data
were confirmed in December 2022.
Statistical analysis
Continuous variables are presented as mean ± standard devi-
ation. Non-normally distributed variables are presented as
medians (interquartile range). Categorical variables are pre-
sented as frequencies or percentages. The clinical characteris-
tics were compared between the survival group and all-cause
death group using Student’sttest, the Mann–Whitney Utest,
or the chi-squared test. Univariate and multivariate Cox
proportional hazard analyses were performed to identify the
independent parameters related to all-cause death and to
assess the degree of prognostic association. High-sensitivity
cardiac troponin T (hs-cTnT) and B-type natriuretic peptide
(BNP) concentrations were converted to log-transformed
TnT and log-transformed BNP in the Cox proportional hazard
analyses. Variables with a P-value of <0.05 in the univariate
Cox hazard analyses model and which might be clinically im-
portant were incorporated in the multivariable Cox hazard
analysis. Receiver operating characteristic curves were con-
structed, and the area under the curve was calculated to as-
sess the ability of RASr and BNP to predict all-cause death
and to determine the cutoff values for predicting all-cause
death. Kaplan–Meier analysis was used to determine the cu-
mulative incidence of all-cause death, and the log-rank test
was used to compare the incidence of all-cause death be-
tween the high and low RASr groups, and the BNP groups.
Statistical analyses were performed with SPSS for Windows,
version 24.0 (IBM Corp., Armonk, NY, USA). A two-tailed P-
value of <0.05 denoted a statistically significant difference.
Results
Diagnosis of immunoglobulin light-chain cardiac
amyloidosis
Among the 72 enrolled patients, 11 patients underwent
endomyocardial biopsy, of whom 10 patients had AL amyloid
Figure 2 Representative example of RA measurement in patients with AL cardiac amyloidosis. White arrow shows RA strain during reservoir phase.
RA, right atrial; AL cardiac amyloidosis, immunoglobulin light-chain cardiac amyloidosis.
RASr and BNP in AL amyloidosis 1615
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

deposition in the heart. In the other 62 patients, AL amyloid
deposition was confirmed in other tissues (skin or abdominal
fat pad, n= 24, gastrointestinal tract, n= 29, kidney, n=9,
other tissues, n= 4). Cardiac amyloidosis was defined based
on amyloid deposition in the myocardium (n= 10) or with
typical findings on cardiac magnetic resonance imaging
(n= 36) or echocardiography (IVSTd >12 mm) (n= 26).
Comparison of clinical characteristics between
the all-cause death and survival groups
During a median follow-up of 403 days (interquartile range,
146–1195 days), 31 deaths occurred (heart failure, n= 16;
out-of-hospital sudden death, n= 3; ventricular arrhythmia,
n= 2; infection, n= 2; renal failure, n= 2; general weakness,
n= 2; intestinal perforation, n= 1; multiple myeloma, n=1;
cerebral infarction, n= 1; and unknown cause, n= 1). No pa-
tients received cardiac transplant. Table
1
shows the clinical
characteristics in the all-cause death group and the survival
group. The rate of stage II was significantly lower, and the
rate of stage IIIb was significantly higher, in the all-cause
death group versus the survival group. The rate of hospitaliza-
tion for heart failure before diagnosis of AL cardiac amyloid-
osis was significantly higher in the all-cause death group
versus the survival group. The rate of New York Heart Associ-
ation (NYHA) class I and II were significantly lower, and NYHA
class III and IV were significantly higher in the all-cause death
group vs. the survival group. Among the laboratory findings,
the estimated glomerular filtration rate was significantly
lower, and BNP and hs-cTnT were significantly higher, in the
all-cause death group versus the survival group. Among the
conventional echocardiographic findings, LVEF, RV fractional
area change (RVFAC), and tricuspid annular plane systolic ex-
cursion (TAPSE) were significantly lower, and the LA volume
index, IVSTd, E/e′ratio, and the rate of mitral regurgitation
were significantly higher in the all-cause death group versus
the survival group. Among the two-dimensional speckle-
tracking echocardiographic findings, LV-GLS, LASr, RV-GLS,
and RASr were significantly lower in the all-cause death group
versus the survival group. Regarding cardiac and haematolog-
ical treatments, the rates of bortezomib and daratumumab
administration were significantly lower in the all-cause death
group versus the survival group.
Cox proportional hazard analysis for all-cause
death
As shown in Table
2
a, the univariate Cox proportional hazard
analysis showed that 20 variables were significantly associ-
ated with higher/lower mortality: log-transformed TnT, log-
transformed BNP, estimated glomerular filtration rate, stage
II, stage IIIb, LAVI, IVSTd, LVEF, E/e′ratio, RVFAC, TAPSE,
mitral regurgitation, tricuspid regurgitation, LV-GLS, LASr,
RV-GLS, RASr, beta-blocker use, bortezomib use, and
daratumumab use. Considering the internal correlation and
the number of patients in our study, we created five models
to perform multivariate Cox proportional hazard analysis
(Table
2
b). RASr was significantly and independently associ-
ated with all-cause death after adjusting for RVFAC, TAPSE,
and RV-GLS (Model 1), RV-GLS, LV-GLS and LASr (Model 2),
conventional echocardiographic findings (Model 3), conven-
tional prognostic risk factors (Model 4), and medications
(Model 5).
Correlation between right atrial strain during the
reservoir phase and the other echocardiographic
findings
Table
3
shows the correlation between RASr and echocardio-
graphic findings in patients with AL cardiac amyloidosis. Var-
ious echocardiographic findings were significantly correlated
with RASr. In particular, LV-GLS, LASr, and RV-GLS were signif-
icantly correlated with RASr (LV-GLS, r= 0.71, P<0.01; LASr,
r= 0.64, P<0.01; RV-GLS, r= 0.82, P<0.01).
Receiver operating characteristic curve analysis
for all-cause death
Receiver operating characteristic curve analysis was per-
formed to determine the optimal RASr and BNP cutoff values
for predicting all-cause death in patients with AL cardiac am-
yloidosis. As shown in Figure
3
A, the area under the curve for
RASr for all-cause death was 0.81, and the best cutoff value
for RASr was 16.4% (sensitivity, 66%; specificity, 84%). In con-
trast, the area under the curve for BNP for all-cause death
was 0.82 (Figure
3
B), and the best cutoff value for BNP was
311.2 pg/mL (sensitivity, 83%; specificity, 78%).
Follow-up of patients with high and low right
atrial strain during the reservoir phase values or
high and low B-type natriuretic peptide values
We divided the patients into two groups using the best cutoff
value for RASr into a high RASr group (≥16.4%, n= 32) and
low RASr group (<16.4%, n= 40). Kaplan–Meier analysis
demonstrated a significantly higher risk of all-cause death in
patients with low versus high RASr (P<0.01, log-rank test)
(Figure
4
A). We also divided the patients into two groups
using the best cutoff value for BNP into a high BNP group
(≥311.2 pg/mL, n= 33) and low BNP group (<311.2 pg/mL,
n= 36). Kaplan–Meier analysis demonstrated a significantly
higher risk of all-cause death in patients with high versus
low BNP (P<0.01, log-rank test) (Figure
4
B).
1616 H. Usuku et al.
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

Table 1 Clinical characteristics between all-cause death group and event-free group
Event-free group (n= 41) All-cause death group (n= 31) P-value
Baseline clinical characteristics
Age, years 67.0 ± 10.0 70.4 ± 8.8 0.14
Male sex, n(%) 27 (66) 20 (65) 0.91
Body mass index, kg/m
2
22.2 ± 4.3 21.5 ± 3.2 0.48
Past medical history
Hypertension, n(%) 18 (44) 7 (23) 0.06
Diabetes mellitus, n(%) 6 (15) 2 (6) 0.27
Dyslipidaemia, n(%) 9 (22) 5 (16) 0.54
Current smoking, n(%) 2 (5) 1 (3) 0.75
Arial fibrillation, n(%) 5 (12) 6 (19) 0.40
ICD, n(%) 3 (7) 3 (10) 0.72
Pacemaker, n(%) 4 (10) 5 (16) 0.42
Stage I, n(%) 4/37 (11) 3/28 (11) 0.99
Stage II, n(%) 11/37 (30) 2/28 (7) <0.05
Stage IIIa, n(%) 20/37 (54) 9/28 (32) 0.08
Stage IIIb, n(%) 2/37 (5) 14/28 (50) <0.01
Systolic blood pressure, mmHg 115.3 ± 16.6 101.7 ± 15.3 <0.01
Diastolic blood pressure, mmHg 66.8 ± 11.6 63.0 ± 11.2 0.18
Hospitalization for heart failure, n(%) 13 (32) 18 (58) <0.05
NYHA class 1, n(%) 19 (46) 4 (13) <0.01
NYHA class II, n(%) 14 (34) 3 (10) <0.05
NYHA class III, n(%) 8 (20) 16 (52) <0.01
NYHA class IV, n(%) 0 (0) 8 (26) <0.01
Laboratory findings
Haemoglobin level, g/dL 12.7 ± 2.4 12.1 ± 2.0 0.27
eGFR, mL/min/1.73 m
2
59.4 ± 24.4 48.2 ± 21.0 <0.05
BNP, pg/mL 123 [81–310] (n= 41) 725 [360–1312] (n= 30) <0.01
Hs-cTnT, ng/mL 0.05 [0.03–0.08] (n= 37) 0.12 [0.07–0.18] (n= 29) <0.01
C-reactive protein, mg/L 0.13 [0.05–0.29] 0.21 [0.05–0.65] 0.39
Difference FLC 257 [72–716] (n= 39) 403 [183–1105] (n= 18) 0.20
Conventional echocardiographic findings
LAVI, mL/m
2
46.7 ± 21.5 59.2 ± 22.7 <0.05
IVSTd, mm 13.0 ± 2.1 14.3 ± 2.8 <0.05
LVPWTd, mm 12.8 ± 2.1 13.8 ± 2.1 0.06
LVEF, % 60.6 ± 7.6 53.6 ± 9.9 <0.01
E/A 1.36 ± 1.17 (n= 37) 1.92 ± 1.36 (n= 25) 0.09
E/e′ratio 18.2 ± 7.4 24.6 ± 10.8 <0.01
RVFAC, % 29.4 ± 7.4 21.0 ± 8.8 <0.01
TAPSE, mm 18.0 ± 5.1 13.7 ± 4.7 <0.01
RA area, cm
2
16.4 ± 5.5 18.6 ± 5.4 0.10
AS (%) 1 (2) 0 (0) 0.38
MS (%) 0 (0) 1 (3) 0.25
MR (%) 1 (2) 8 (26) <0.01
TR (%) 1 (2) 4 (13) 0.08
Two-dimensional speckle tracking echocardiographic findings
LV-GLS, % 11.8 ± 3.8 8.5 ± 4.3 <0.01
LASr, % 14.3 ± 8.1 8.8 ± 7.1 <0.01
RV-GLS, % 16.4 ± 3.9 11.6 ± 5.1 <0.01
RASr, % 20.7 ± 9.5 10.2 ± 7.3 <0.01
Cardiac treatment
RAS inhibitor, n(%) 9 (22) 11 (35) 0.20
Beta-blocker, n(%) 5 (12) 8 (26) 0.14
Diuretic, n(%) 24 (59) 24 (77) 0.09
Haematological treatment
Bortezomib, n(%) 17 (41) 6 (19) <0.05
Daratumumab, n(%) 32 (78) 6 (19) <0.01
P-values were obtained by Student’st-test, Mann–Whitney Utest or chi-squared test.
AS, aortic stenosis; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; FLC, free light chain; GLS, global longitu-
dinal strain; hs-cTnT, high sensitivity cardiac troponin T; ICD, implantable cardioverter defibrillator; IVSTd, interventricular septal thickness
in diastole; LASr, left atrial strain during reservoir phase; LAVI, left atrial volume index; LV, left ventricle; LVEF, left ventricular ejection frac-
tion; LVPWTd, left ventricular posterior wall thickness in diastole; MR, mitral regurgitation; MS, mitral stenosis; NYHA, New York Heart As-
sociation; RA, right atrium; RAS, renin angiotensin system; RASr, right atrium strain during reservoir phase; RV, right ventricle; RVFAC,
right ventricular fractional area change; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation.
RASr and BNP in AL amyloidosis 1617
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DOI: 10.1002/ehf2.14710

Next, we divided the patients into four groups using
Lilleness et al.’s survival staging system, as follows: survival
stage I, II, IIIa, and IIIb. The hazard ratio of all-cause death
using stage I as a reference was 5.31 (95% CI: 1.45–19.45,
P<0.05) for stage IIIb, but 0.78 (95% CI; 0.21–2.93,
P= 0.71) for stage IIIa and 0.36 (95% CI: 0.06–2.16,
P= 0.26) for stage II (Table
4
). Kaplan–Meier analysis demon-
strated no significant difference in all-cause death rates
between stage I, stage II, and stage IIIa (Figure
4
C).
We devised a new survival staging score by adding 1 point
if the RASr level decreased or BNP level increased more than
the respective cut-off value. The hazard ratio for all-cause
mortality, using score 0 as a reference, was 5.95 (95% CI:
1.19–29.79, P<0.05) for score 1 and 23.29 (95% CI: 5.37–
100.98, P<0.01) for score 2 (Table
4
). Kaplan–Meier analysis
demonstrated clear differences in all-cause death between
score 0, 1 and 2 groups (Figure
4
D).
Discussion
The present study reported two new findings: (i) RASr by
two-dimensional speckle-tracking echocardiography was an
important prognostic factor in patients with AL cardiac amy-
loidosis after adjusting for various factors including RVFAC,
TAPSE, LV-GLS, RV-GLS, conventional echocardiographic find-
ings, conventional prognostic risk factors, and medications,
and (ii) the new staging system using RASr and BNP was use-
ful to stratify the prognosis in these patients.
Singulane et al. reported that RALS was significantly asso-
ciated with worse prognosis in AL cardiac amyloidosis.
20
However, the study did not compare RALS with other LS
values. Huntjens et al. also revealed the usefulness of RALS
to evaluate outcomes in patients with cardiac amyloidosis.
21
However, RA strain did not have greater prognostic power
compared with other LS values. The study by Huntjens
et al. enrolled patients with various types of amyloid cardio-
myopathy. Because the prognosis depends on the type of
amyloid cardiomyopathy,
22
specific evaluations should be
performed on the basis of each type of amyloid cardiomyop-
athy. Therefore, in the present study, we enrolled only
patients with AL cardiac amyloidosis. To our knowledge,
our study is the first to reveal the superiority of RALS over
LV-GLS, LALS, and RV-GLS to predict all-cause mortality in
these patients.
The normal mechanical function of the RA provides suffi-
cient return of blood to the heart, avoids venous congestion,
and protects the upstream organs.
23
The sinoatrial node gen-
erates the cardiac impulse, and endocrine function is pivotal
in volume regulation in response to acute myocyte stretch
and neurohumoral activation.
24
Previous studies showed that
RA structural and functional remodelling are prevalent in pa-
tients with heart failure (HF), pulmonary arterial hyperten-
sion, and hypertrophic cardiomyopathy.
25–27
Furthermore,
RA structural and functional remodelling are reported risk
predictors in several studies.
28,29
The RA also plays an important role in modulating the in-
teractions between the performance of the other heart
chambers. Therefore, in patients with AL cardiac amyloidosis,
the RA is affected by both direct amyloid deposition and the
other chambers. The present study revealed that RASr was
significantly correlated with RV-GLS and LASr, indicating that
RA function was affected by RV function and LA function. Be-
cause RV dysfunction can be a late consequence of changes
in the pulmonary circulation that result from HF, changes in
Table 2a Univariate cox proportional hazards model for all-cause
death
Univariate analysis
HR (95% CI) P-value
Age per 1 year 1.04 (1.00–1.08) 0.06
Male sex/yes 0.98 (0.46–2.06) 0.95
Body mass index per 1 kg/m
2
0.96 (0.88–1.05) 0.39
Hypertension/yes 0.48 (0.21–1.12) 0.09
Diabetes mellitus/yes 0.43 (0.10–1.83) 0.26
Dyslipidaemia/yes 0.67 (0.26–1.75) 0.41
Atrial fibrillation/yes 1.83 (0.74–4.51) 0.19
Current smoking/yes 0.71 (0.10–5.25) 0.74
Haemoglobin level per 1 g/dL 0.92 (0.79–1.08) 0.31
Ln TnT per 1 2.12 (1.42–3.15) <0.01
Ln BNP per 1 3.19 (2.07–4.92) <0.01
eGFR per 1 mL/min/1.73 m
2
0.98 (0.97–1.00) <0.05
Difference FLC per 1 1.00 (1.00–1.00) 0.63
Stage I/yes 0.79 (0.24–2.63) 0.70
Stage II/yes 0.22 (0.05–0.93) <0.05
Stage IIIa/yes 2.96 (1.12–7.80) 0.07
Stage IIIb/yes 9.58 (4.29–21.37) <0.01
LAVI per 1 mL/m
2
1.02 (1.00–1.04) <0.05
IVSTd per 1 mm 1.20 (1.04–1.38) <0.05
LVPWTd per 1 mm 1.15 (0.99–1.34) 0.08
LVEF per 1% 0.94 (0.91–0.97) <0.01
E/e′ratio per 1 1.05 (1.02–1.09) <0.01
RVFAC per 1% 0.91 (0.87–0.95) <0.01
TAPSE per 1 mm 0.86 (0.80–0.93) <0.01
RA area per 1 cm
2
1.04 (0.99–1.10) 0.15
Mitral regurgitation/yes 5.67 (2.36–13.63) <0.01
Tricuspid regurgitation/yes 4.42 (1.51–12.96) <0.01
LV-GLS per 1% 0.82 (0.74–0.91) <0.01
LASr per 1% 0.91 (0.85–0.97) <0.01
RV-GLS per 1% 0.82 (0.76–0.89) <0.01
RASr per 1% 0.87 (0.83–0.92) <0.01
RAS inhibitor/yes 1.62 (0.77–3.42) 0.20
Beta-blocker/yes 2.42 (1.07–5.51) <0.05
Diuretics/yes 2.13 (0.87–5.22) 0.10
Bortezomib/yes 0.36 (0.14–0.90) <0.05
Daratumumab/yes 0.11 (0.42–0.26) <0.01
P-value was obtained by the univariate Cox hazard analyses model.
BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtra-
tion rate; FLC, free light chain; GLS, global longitudinal strain;
IVSTd, interventricular septal thickness in diastole; LASr, left atrial
strain during reservoir phase; LAVI, left atrial volume index; Ln, nat-
ural logarithm; LV, left ventricle; LVEF, left ventricular ejection frac-
tion; LVPWTd, left ventricular posterior wall thickness in diastole;
RA, right atrium; RAS, renin angiotensin system; RASr, right atrium
strain during reservoir phase; RV, right ventricle; RVFAC, right ven-
tricular fractional area change; TAPSE, tricuspid annular plane sys-
tolic excursion; TnT, troponin T.
1618 H. Usuku et al.
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

RA function can aid in the assessment of right heart function.
Therefore, RA function is one of the responses to changes in
RV compliance and diastolic function early in the course of
HF. Additionally, LV dysfunction worsens RV dysfunction
because of pulmonary venous hypertension, ventricular in-
terdependence, neurohormonal interactions, and RV myo-
cardial ischemia.
30
LA dysfunction is usually correlated with
worse impairment of LV diastolic function because high LV
filling pressure leads to deterioration of LA function as a
result of hemodynamic overload and mechanical stretching
of the LA wall.
31
Therefore, RA function is thought to be
affected by direct LA and RV dysfunction and indirect LV
dysfunction. In addition, amyloid deposition occurs in all
chambers.
11
Because RA is the lowest pressured chamber,
the effect of amyloid deposition may be higher in RA than
in other chambers. We speculate that RASr could provide
greater prognostic power compared with LV-GLS, LASr, and
RV-GLS in patients with AL cardiac amyloidosis because RA
is the lowest pressured chamber and RA dysfunction might
reflect the overall burden of LV, LA, and RV dysfunction,
and amyloid deposition.
The RA is now being recognized as more than a passive fill-
ing chamber. During the cardiac cycle, the RA serves three
primary functions: (i) a reservoir function, (ii) a conduit func-
tion, and (iii) a booster pump function.
25
The present study
revealed the usefulness of RA reservoir function to evaluate
the prognosis in patients with AL cardiac amyloidosis. How-
ever, we could not evaluate conduit function and booster
pump function because many patients’data did not include
booster pump function. It is well known that the rate of atrial
fibrillation is high in patients with amyloid cardiomyopathy.
32
Table 2b Multivariate Cox proportional hazards model for all cause death
Model 1 Model 2 Model 3
HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value
RVFAC per 1% 0.98 (0.91–1.05) 0.50
TAPSE per 1 mm 0.96 (0.87–1.05) 0.37
RV-GLS per 1% 0.98 (0.83–1.16) 0.82 0.94 (0.82–1.09) 0.43
LV-GLS per 1% 0.96 (0.83–1.12) 0.63
LASr per 1% 1.00 (0.94–1.06) 0.89
LAVI per 1 mL/m
2
0.99 (0.97–1.02) 0.54
IVSTd per 1 mm 1.30 (1.01–1.67) <0.05
LVEF per 1% 1.01 (0.94–1.09) 0.85
E/e′/1 0.97 (0.91–1.04) 0.37
Mitral regurgitation/yes 39.11 (6.91–221.43) <0.01
Tricuspid regurgitation/yes 7.45 (1.27–43.72) <0.05
RASr per 1% 0.91 (0.84–0.98) <0.05 0.91 (0.83–0.99) <0.05 0.87 (0.80–0.95) <0.01
Model 4 Model 5
HR (95% CI) P-value HR (95% CI) P-value
Ln TnT/1 1.22 (0.61–2.47) 0.57
Ln BNP/1 2.10 (1.17–3.79) <0.05
eGFR per 1 mL/min/1.73 m
2
1.00 (0.98–1.02) 0.64
Beta-blocker/yes 1.62 (0.69–3.79) 0.27
Bortezomib/yes 0.33 (0.12–0.95) <0.05
Daratumumab/yes 0.12 (0.04–0.31) <0.01
RASr per 1% 0.93 (0.87–1.00) <0.05 0.90 (0.85–0.94) <0.01
P-value was obtained by the multivariate Cox hazard analysis.
eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; IVSTd, interventricular septal thickness in diastole; LASr, left
atrial strain during reservoir phase; LAVI, left atrial volume index; Ln, natural logarithm; LV, left ventricle; LVEF, left ventricular ejection
fraction; RASr, right atrium strain during reservoir phase; RV, right ventricle; RVFAC, right ventricular fractional area change; TAPSE, tricus-
pid annular plane systolic excursion; TnT, troponin T; BNP, B-type natriuretic peptide.
Table 3 Correlation between RASr and the other
echocardiographic findings
Variables RP-value
LAVI per 1 mL/m
2
0.22 0.07
IVSTd per 1 mm 0.31 <0.01
LVPWTd per 1 mm 0.38 <0.01
LVEF per 1% 0.51 <0.01
E/A ratio per 1 0.40 <0.01
E/e′ratio per 1 0.45 <0.01
RVFAC per 1% 0.65 <0.01
TAPSE per 1 mm 0.57 <0.01
RA area per 1cm
2
0.45 <0.01
LV-GLS per 1% 0.71 <0.01
LASr per 1% 0.64 <0.01
RV-GLS per 1% 0.82 <0.01
P-value was obtained by using Pearson’s method.
99m
Tc-PYP scintigraphy,
99m
Tc-pyrophosphate scintigraphy; IVSTd,
interventricular septal thickness in diastole; LAVI, left atrial volume
index; LVEF, left ventricular ejection fraction; LVPWTd, left ventric-
ular posterior wall thickness in diastole; RVFAC, right ventricular
fractional area change; RVFWLS, right ventricular free wall longitu-
dinal strain; RV-GLS, right ventricular global longitudinal strain;
TAPSE, tricuspid annular plane systolic excursion.
RASr and BNP in AL amyloidosis 1619
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

As a result, clinically, there is no booster pump function in
many patients with amyloid cardiomyopathy. In our present
study, the rate of atrial fibrillation was not different between
the all-cause death group and event-free group, indicating
the prognostic implications of abnormal RASr is likely inde-
pendent of atrial fibrillation. Therefore, the use of RASr is
clinically relevant as a prognostic factor in patients with AL
cardiac amyloidosis in the clinical setting.
A previous survival staging system using BNP and cardiac
troponin predicted a poor prognosis in AL cardiac
amyloidosis.
6
However, in the present study, there were no
significant differences in prognosis between stage I, stage II,
and stage IIIa, using the previous system. Our study revealed
that hs-cTnT was not significantly useful to predict the prog-
nosis in patients with AL cardiac amyloidosis, which might
be the reason why the previous survival staging system was
Figure 3 Receiver operator characteristic curve analysis of RASr (A) and BNP (B) for predicting all-cause death. RASr, right atrial strain during the res-
ervoir phase; BNP, B-type natriuretic peptide; AUC, area under the curve.
1620 H. Usuku et al.
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

not useful in the early stage. In contrast, the new staging
system described in this study, which uses RASr and BNP
clearly stratified the enrolled patients’prognostic risk into
three groups. This was because RASr was significantly and
independently associated with prognosis in patients with AL
cardiac amyloidosis after adjusting for BNP. Therefore, this
new staging system might be useful even in the early stage
of AL cardiac amyloidosis to stratify patients’prognosis.
Figure 4 Kaplan–Meier curves for all-cause death in patients with AL cardiac amyloidosis with high or low RASr (A) and low or high BNP (B) based on a
previously reported staging system: stage I, II, IIIa and IIIb (C), and the new staging system: score 0, 1, and 2 (D). AL cardiac amyloidosis, immunoglob-
ulin light-chain cardiac amyloidosis; RASr, right atrial strain during the reservoir phase.
Table 4 Cox proportional hazards model for all cause death by stage and score
Stage HR (95% CI) P-value Score HR (95% CI) P-value
I Ref. Ref.
II 0.36 (0.06–2.16) 0.26 0 5.95 (1.19–27.79) <0.05
IIIa 0.78 (0.21–2.93) 0.71 1 23.29 (5.37–100.98) <0.01
IIIb 5.31 (1.45–19.45) <0.05 2
P-value was obtained by the Cox hazard analysis model.
RASr and BNP in AL amyloidosis 1621
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

The addition of daratumumab to classical medical therapy
was recently shown to be associated with survival free from
major organ deterioration or hematologic progression in pa-
tients with newly diagnosed AL amyloidosis.
33
Therefore,
daratumumab combination therapy represents an important
emerging first-line treatment option for patients with sys-
temic AL amyloidosis. However, few data are available
regarding prognostic echocardiographic factors in patients
with daratumumab therapy. Our study revealed that RALS
was independently associated with all-cause mortality even
after adjusting for administration of daratumumab therapy.
This result indicates that RALS is an important prognostic
factor even in patients with daratumumab therapy. Thus,
daratumumab therapy should be started in the early stage
of AL cardiac amyloidosis, when RA function is fully
preserved. Cardiac transplantation is one of the other ther-
apeutic options for severe AL cardiac amyloidosis.
34
In
Japan, however, cardiac transplantation is not usually
performed in patients with AL cardiac amyloidosis because
almost of these patients are high age and their disease pro-
gression is generally rapid. Therefore, we could not evaluate
the effect of cardiac transplantation on the usefulness of
RALS in patients with AL cardiac amyloidosis in our present
study.
We previously reported the usefulness of LA and RV strain
for prognostic factor in patients with ATTRwt-CM.
12,13
However, we had no data about the usefulness of RALS in
these patients. Therefore, we have to evaluate the usefulness
of RALS for prognostic factor in patients with ATTR-CM in the
future.
Study limitations
This study has several limitations. First, this was a retrospec-
tive single-centre study that included a small number of
patients with AL cardiac amyloidosis. This was important
limitation in our present study. Therefore, further multicentre
prospective studies with more patients are needed to
validate our results. Second, echocardiographic images were
obtained using several different brands of ultrasound ma-
chines. We performed the two-dimensional speckle-tracking
echocardiography analysis using vendor-independent soft-
ware (TomTec Image-Arena
™
). Although significant correla-
tions have been shown in the LS values analysed using
vendor-independent software for paired images obtained
from different ultrasound machines,
35
inter-machine variabil-
ity may still have affected our study results. Third, several
patients were diagnosed with AL cardiac amyloidosis before
the RV-focused apical four-chamber view was recommended.
Therefore, we had no choice but to use the apical
four-chamber view to evaluate RASr and RV-GLS in these pa-
tients. In addition, the e′lateral line was not measured in sev-
eral patients because the patients were diagnosed with AL
cardiac amyloidosis before the e′lateral line was recom-
mended. Therefore, we used only the e′septal line to evalu-
ate LV diastolic function in the present study. Fourth, the rate
of stage 3b was 50% in all-cause death group. In contrast, the
rate of stage 3b was only 5% in event-free group. In addition,
the components of previous survival staging system: BNP and
hs-cTnT were significantly associated with all-cause death by
univariate Cox proportional hazard model. These results indi-
cated that many patients in all-cause death group was in the
advanced stage and those in event-free group were in the
early stage, and most of these two populations were not
overlapping. In our present study, however, RASr was signifi-
cantly and independently associated with all-cause death
adjusting for BNP and hs-cTnT. Thus, RASr might be a signifi-
cant and independent prognostic factor after adjusting for
previous survival staging system in patients with AL cardiac
amyloidosis. Fifth, only 6 patients in the all-cause death
group received daratumumab therapy. Thus, the event-free
survival group received more treatment than the all-cause
death group. This is an important limitation that RASr was a
significant prognostic marker independent of daratumumab
therapy.
Despite these limitations, the present study demonstrated
the importance of RA function estimated by two-dimensional
strain analysis compared with LVLS, LALS, and RVLS, and the
usefulness of new staging system using BNP and RASr in
patients with AL cardiac amyloidosis. We believe that our
results have important clinical value.
Conclusions
RASr has prognostic value in patients with AL cardiac
amyloidosis and provides greater prognostic power than that
of LV-GLS, LASr, and RV-GLS. The new staging system demon-
strated by this study, using RASr and BNP, might be useful for
predicting prognosis in patients with AL cardiac amyloidosis.
Funding
This study was supported in part by a Grant-in-Aid for Scien-
tific Research (grant number 20K17087) from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
to DS; a Grant-in-Aid for Scientific Research (grant number
20K08476) from the Japan Society for the Promotion of Sci-
ence to HU; and a research grant from Pfizer Japan
Incorporated to HU.
1622 H. Usuku et al.
ESC Heart Failure 2024; 11: 1612–1624
DOI: 10.1002/ehf2.14710

Acknowledgements
We thank Jane Charbonneau, DVM, from Edanz (https://jp.
edanz.com/ac) for editing a draft of this manuscript.
Conflict of interest
None declared.
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