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\begin{document}

\title{Ventricular Sigmoid Septum as a Risk Factor for Anthracycline-Induced
Cancer Therapeutics-Related Cardiac Dysfunction in Patients with
Malignant Lymphoma}



\author[1]{Takafumi Nakayama}%
\author[2]{Yoshiko Oshima}%
\author[1]{Yasuhiro Shintani}%
\author[1]{Junki Yamamoto}%
\author[1]{Masashi Yokoi}%
\author[1]{Tsuyoshi Ito}%
\author[1]{Kazuaki Wakami}%
\author[1]{Shuichi Kitada}%
\author[1]{Toshihiko Goto}%
\author[1]{Shigeru Kusumoto}%
\author[1]{Tomonori Sugiura}%
\author[1]{Shinsuke Iida}%
\author[1]{Yoshihiro Seo}%
\affil[1]{Nagoya City University}%
\affil[2]{Toyokawa City Hospital}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
ABSTRACT Background Identifying risk factors for cancer
therapeutics-related cardiac dysfunction (CTRCD) is essential for early
detection and prompt initiation of medial therapy for CTRCD. There has
been no study investigating whether the sigmoid septum is a risk factor
for anthracycline-induced CTRCD. Methods We enrolled 167 patients with
malignant lymphoma who received a CHOP-like regimen from January 2008 to
December 2017 and underwent both baseline and follow-up
echocardiography. Patients with LVEF [?] 50\% were excluded. CTRCD was
defined as [?] 10\% decline in LVEF and LVEF \textless{} 50\% after
chemotherapy. The angle between the anterior-wall of the aorta and the
ventricular septal surface (ASA) was measured to quantify the sigmoid
septum. Results CTRCD was observed in 36 patients (22\%). The average
LVEF and GLS were lower (61.6 vs. 65.0\%, 18.7 vs. 20.3), LV mass index
was higher (101.1 vs. 92.8 g/m2), and ASA was smaller (112.1 vs. 119.4
degree) in patients with CTRCD. In a multivariable Cox proportional
hazard analysis, GLS (HR per 1\% decrease 1.20, 95\% CI 1.07-1.35, P =
0.002), ASA (HR per 1 degree increase 0.97, 95\% CI 0.95-0.99, P =
0.003) and the history of ischemic heart disease (HR 5.13, 95\% CI
1.94-13.56, P = 0.001) were identified as the independent determinants
of CTRCD. C-statistics analysis and integrated discrimination
improvement proved the significant incremental value of ASA for
developing CTRCD. Conclusion Smaller ASA was the independent risk factor
and had significant incremental value for CTRCD in patients with
malignant lymphoma who received the CHOP-like regimen.%
\end{abstract}%



\sloppy


\textbf{Original Investigations}

\textbf{Title:}

Ventricular Sigmoid Septum as a Risk Factor for Anthracycline-Induced
Cancer Therapeutics-Related Cardiac Dysfunction in Patients with
Malignant Lymphoma

\textbf{Authors:}

Takafumi Nakayama\textsuperscript{a}, MD, PhD, Yoshiko
Oshima\textsuperscript{b}, MD, Yasuhiro Shintani\textsuperscript{a}, MD,
PhD, Junki Yamamoto\textsuperscript{a}, MD, PhD, Masashi
Yokoi\textsuperscript{a}, MD, Tsuyoshi Ito\textsuperscript{a}, MD, PhD,
Kazuaki Wakami\textsuperscript{a}, MD, PhD, Shuichi
Kitada\textsuperscript{a}, MD, PhD, Toshihiko Goto\textsuperscript{a},
MD, PhD, Shigeru Kusumoto\textsuperscript{b}, MD, PhD, Tomonori
Sugiura\textsuperscript{a}, MD, PhD, Shinsuke Iida\textsuperscript{b},
MD, PhD, Yoshihiro Seo\textsuperscript{a}, MD, PhD

\textbf{Affiliations:}

\textsuperscript{a} Department of Cardiology, Nagoya City University
Graduate School of Medical Sciences

1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

\textsuperscript{b} Department of Hematology and Oncology, Nagoya City
University Graduate School of Medical Sciences

1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

\textbf{Corresponding author contact information:}

Correspondence: Yoshihiro Seo, MD, PhD

Department of Cardiology, Nagoya City University Graduate School of
Medical Sciences

1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan

Phone: +81-52-853-8221; Fax: +81-52-852-3796

E-mail: yo-seo@med.nagoya-cu.ac.jp

\textbf{Running head:}

Sigmoid-septum and CTRCD in ML patients

\textbf{Total word count:}

4,439 words from introduction to references.

\textbf{Declarations of interest:}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.



\textbf{ABSTRACT}

\textbf{Background}

Identifying risk factors for cancer therapeutics-related cardiac
dysfunction (CTRCD) is essential for early detection and prompt
initiation of medial therapy for CTRCD. There has been no study
investigating whether the sigmoid septum is a risk factor for
anthracycline-induced CTRCD.

\textbf{Methods}

We enrolled 167 patients with malignant lymphoma who received a
CHOP-like regimen from January 2008 to December 2017 and underwent both
baseline and follow-up echocardiography. Patients with LVEF [?] 50\% were
excluded. CTRCD was defined as [?] 10\% decline in LVEF and LVEF
\textless{} 50\% after chemotherapy. The angle between the anterior-wall
of the aorta and the ventricular septal surface (ASA) was measured to
quantify the sigmoid septum.

\textbf{Results}

CTRCD was observed in 36 patients (22\%). The average LVEF and GLS were
lower (61.6 vs. 65.0\%, 18.7 vs. 20.3), LV mass index was higher (101.1
vs. 92.8 g/m\textsuperscript{2}), and ASA was smaller (112.1 vs. 119.4
degree) in patients with CTRCD. In a multivariable Cox proportional
hazard analysis, GLS (HR per 1\% decrease 1.20, 95\% CI 1.07-1.35, P =
0.002), ASA (HR per 1 degree increase 0.97, 95\% CI 0.95-0.99, P =
0.003) and the history of ischemic heart disease (HR 5.13, 95\% CI
1.94-13.56, P = 0.001) were identified as the independent determinants
of CTRCD. C-statistics analysis and integrated discrimination
improvement proved the significant incremental value of ASA for
developing CTRCD.

\textbf{Conclusion}

Smaller ASA was the independent risk factor and had significant
incremental value for CTRCD in patients with malignant lymphoma who
received the CHOP-like regimen.

\textbf{Keywords:}

Cancer therapeutics-related cardiac dysfunction, anthracycline-induced
cardiotoxicity, sigmoid septum, aorto-septal angle



\textbf{ABBREVIATIONS}

ASA = the angle between the anterior-wall of the aorta and the
ventricular septal surface (aorto-septal angle)

B-M ratio = the ratio of basal to mid interventricular septal diameter
(basal-mid ratio)

CHOP = cyclophosphamide, doxorubicin, vincristine and prednisolone

CI = confidence interval

CTRCD = Cancer therapeutic-related cardiac dysfunction

DUST = discrete upper septal thickening

HR = hazard ratio

IDI = integrated discrimination improvement

LVEF = left ventricular ejection fraction

LVMi = left ventricular mass index

ML = malignant lymphoma

NRI = net reclassification index

R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and
prednisolone

\textbf{INTRODUCTION}

Anthracycline is an effective chemotherapeutic agent for several kinds
of malignant tumors, particularly in patients with malignant lymphoma
(ML) and breast cancer. \textsuperscript{1-3} In contrast,
anthracycline-induced cancer therapeutic-related cardiac dysfunction
(CTRCD), defined by a decline in left ventricular ejection fraction
(LVEF), often causes poor clinical outcomes and low quality of life in
patients with cancer. \textsuperscript{4-9} Identification of baseline
risk factors for CTRCD is vital for early detection and prompt
initiation of medical therapy, which are essential for improving left
ventricular (LV) contraction after CTRCD
develops.\textsuperscript{10-12} Several baseline risk factors have been
clarified in previous studies, including baseline LVEF, global
longitudinal strain (GLS), age, general cardiovascular risk factors, a
history of cardiovascular disease. \textsuperscript{4,11,13-15}Recently,
LV hypertrophy was recognized as a risk factor for CTRCD in ML patients
\textsuperscript{16}, suggesting LV morphologic remodeling also
represents an accumulated myocardial injury that may cause a vulnerable
condition for CTRCD. On the other hand, the sigmoid septum, known as a
synonym of discrete upper septal thickening, is considered one of LV
morphologic remodeling. The previous investigation reported that the
sigmoid septum was significantly related to LV diastolic
dysfunction.\textsuperscript{17} However, no one clarified the
association of the sigmoid septum with the incidence of CTRCD.

In the current study, we focused on the presence of the sigmoid septum
and aimed to reveal its impact on anthracycline-induced CTRCD in
patients with ML who received the CHOP-like regimen.

\textbf{MATERIALS AND METHODS}

\textbf{Study population}

All ML patients who received the CHOP-like regimen (cyclophosphamide +
doxorubicin + vincristine + prednisolone \selectlanguage{ngerman}± rituximab) from January 2008
to December 2017 at Nagoya City University Hospital were retrospectively
reviewed. The dosing and schedule for the CHOP-like regimen were
standardized in this cohort. From this group, patients who underwent a
baseline echocardiographic examination and at least one or more
follow-up examinations were enrolled in the current study (Figure 1).
Patients with LVEF \textless{} 50\% at baseline but no echocardiographic
images of adequate quality were excluded. The current study was the
sub-analysis of a previous study in which we described the clinical
features of anthracycline-induced CTRCD \textsuperscript{18}.

\textbf{Study protocol}

We retrospectively collected patients' clinical characteristics,
including age, sex, body mass index, general cardiovascular risk
factors, past history, laboratory data, chemotherapeutic regimen,
performance status, and echocardiographic parameters from their medical
records. The chemotherapeutic regimen, performance status, and dose of
anthracycline were assessed by two hematologists. Patients with
intravascular large B-cell lymphoma (IVL) and primary mediastinal large
B cell lymphoma (PMLBCL) were enrolled as a subtype of diffuse large
B-cell lymphoma (DLBCL) in the current study. Echocardiographic
parameters and the incidences of symptomatic heart failure and
cardiovascular death were obtained and assessed by two cardiologists in
a blinded manner. In the current study, CTRCD was defined as a decline
in LVEF of 10\% or more from baseline and LVEF \textless{} 50\% in the
follow-up study. \textsuperscript{9}

Cardiovascular risk factors were defined as hypertension, dyslipidemia,
diabetes mellitus, and a history of smoking. Each cardiovascular risk
factor was defined by the following criteria: hypertension, as a record
of a history of hypertension or being on antihypertensive therapy;
dyslipidemia, as a record of a history of dyslipidemia, serum
low-density lipoprotein cholesterol level \selectlanguage{english}[?] 140 mg/dL, or being on
cholesterol-lowering treatment; and diabetes mellitus, as a record of a
history of diabetes mellitus, HbA1c \selectlanguage{english}[?] 6.5\%, or being on blood
glucose-lowering therapy. History of ischemic heart disease was defined
as a history of myocardial infarction, angina pectoris, or coronary
artery revascularization. The current study was approved by the ethics
committee of our institution (No. 60-19-0125) and was carried out
according to the principles of the Helsinki Declaration.

\textbf{Echocardiography}

Echocardiographic data were measured according to the recommendations of
the American Society of Echocardiography \textsuperscript{19}. However,
avoiding the region of the sigmoid septum, the LV end-diastolic diameter
(LVDd), interventricular septal wall thickness (IVSd), and posterior
wall thickness (PWd) were measured at a mid-ventricular position. LVEF
was calculated by the disk summation method using the TomTec imaging
system (TomTec Imaging System GmbH, Munich, Germany). To avoid a
misdiagnosis of CTRCD, we re-measured LVEF, which was between 40\% to
60\% by the first measurer, by the second measurer (the other of the
first measurer) to assess the accuracy of diagnosis. LV wall thickness
was defined as the mean IVSd and PWd. LV mass was calculated using the
following formula (10): 1.04x{[}(LVDd + IVS + PWd)\textsuperscript{3} --
LVDd\textsuperscript{3}{]}x0.8 + 0.6. The grading of valvular diseases
was assessed according to the guidelines of the Japanese Circulation
Society. \textsuperscript{20}

As morphological parameters, we calculated the ratio of basal to mid
interventricular septal diameter (basal-mid ratio, B-M ratio), and
measured the angle between the anterior-wall of the aorta and the
ventricular septal surface (aorto-septal angle, ASA) in the end
diastolic phase to quantify discrete upper septal thickening (Figure 2).

\textbf{Statistical analysis}

Continuous variables were expressed as mean +- standard deviation.
Continuous variables were compared using unpaired Student's t-test.
Welch's test was used to compare continuous variables with
heteroscedasticity. Categorical variables were analyzed using Pearson's
chi-squared test. Cox proportional hazards analyses were performed to
identify risk factors for the primary endpoint. The common logarithmic
conversion was used when BNP was assessed in Cox proportional hazard
analyses.

The primary endpoint was the incidence of CTRCD, and the initial
time-point for each survival analysis was the first day of the CHOP-like
regimen. Follow-up censoring of all participants was the day of the
first detection of CTRCD or final echocardiographic examination.
Clinical variables recognized as risk factors for CTRCD were analyzed
using univariate Cox proportional hazards analyses. The GLS value was
converted to an absolute value when assessed in Cox proportional hazard
analyses, Kaplan-Meier analyses and Logistic regression analyses. In the
first multivariable Cox proportional hazards analysis, echocardiographic
parameters with p \textless{} 0.05 in the univariate analyses were
analyzed to clarify the independent echocardiography-derived
determinants of the event (multivariable analysis 1). Next, the
independent echocardiographic parameters were adjusted by the clinical
parameters with p \textless{} 0.05 in the univariate analyses as
multivariable analysis 2. Multivariable Cox proportional hazard analyses
were assessed by the forward stepwise method. Youden's index derived
from receiver operating characteristics (ROC) curves were used to
determine the cut-off value for risk factors for the primary endpoint.
Event-free survival curves using the cut-off values were constructed by
Kaplan-Meier analyses, and the log-rank test was used to assess the
significance between curves.

To assess the incremental value of newly recognized risk factors for
CTRCD, we defined two categorized models: model 1 included the risk
factors that were already considered risk factors in a previous study
and were recognized independently for CTRCD in the current study,
whereas model 2 had all independent risk factors identified in the
current study, including newly recognized risk factors. First, we
compared the c-statistics of each model, which was calculated as an area
under the curve (AUC) to assess the utility of new risk factors. Second,
we used the net reclassification index (NRI) and integrated
discrimination improvement (IDI) to evaluate the incremental value of
risk factors newly identified in this study \textsuperscript{21}. In
these analyses, patients with a probability \selectlanguage{english}[?] 0.5 in logistic regression
analyses in each model were considered to have CTRCD.

NRI was calculated according to the following formula:

NRI = {[}P(up\textbar{}D=1) -- P(down\textbar{}D=1){]} --
{[}P(up\textbar{}D=0) -- P(down\textbar{}D=0){]}

where P is the proportion of patients, ``up'' is upward movement defined
as a change into a higher probability of CTRCD based on model 1,
``down'' is downward movement defined as a change in the opposite
direction, and D is the classification of whether CTRCD develops
(developing CTRCD = 1, not developing CTRCD = 0).

IDI was calculated according to the following formula:

IDI = {[}(P\textsubscript{extended}\textbar{}D=1) --
(P\textsubscript{basic}\textbar{}D=1){]} --
1{[}(P\textsubscript{extended}\textbar{}D=0) --
(P\textsubscript{basic}\textbar{}D=0){]}

where P\textsubscript{extended}\textbar{}D=1 and
P\textsubscript{extended}\textbar{}D=0 are the average values of the
predicted probability of developing CTRCD in model 2 for the group that
developed CTRCD and the group that did not, respectively; and
P\textsubscript{basic}\textbar{}D=1 and
P\textsubscript{basic}\textbar{}D=0 are the average values of the
predicted probability of developing CTRCD in model 1 for the group that
developed CTRCD and the group that did not, respectively.

Two-sided P \textless{} 0.05 was considered significant. All analyses
were performed using SPSS ver. 26 (SPSS, Inc., Chicago, IL, USA).

\textbf{RESULTS}

\textbf{Study population}

Of 443 enrolled patients, 14 patients without baseline echocardiography
data and 185 patients without follow-up echocardiography data were
excluded. Fourteen patients with LVEF \textless{} 50\%, 62 patients
whose GLS could not be quantified by tri-plane, and one patient without
any echocardiographic images available for analysis were also excluded.
In the comparison between the patients who underwent GLS measurements
and those who were excluded because they could not have GLS
measurements, no significant differences were observed in basic data and
laboratory data (Table S1).

Finally, 167 patients were eligible for analysis in the current study
(Figure 1). CTRCD was observed in 36 patients (22\%) during the
follow-up period, which was a median 305 days (IQR: 171-837). The mean
and median number of follow-up echocardiographic examinations were 3.0 +-
2.6 and 2 (IQR, 1-4). Median interval duration of all echocardiographic
follow-up study was 112 days (IQR, 50-238).

\textbf{Baseline characteristics}

The baseline characteristics of eligible patients are summarized in
Table 1. No significant differences were found in baseline
characteristics between patients with and without CTRCD except for the
prevalence of prior ischemic heart disease. Most patients (83\%)
received the R-CHOP regimen, and the remaining received the CHOP
regimen. Patients with DLBCL were 67\% (n=111), including 4 and 2
patients with IVL and PMLBCL, respectively. The mean cumulative dose of
doxorubicin was almost within the accurate range of 291.5 +- 95.3
mg/m\textsuperscript{2} (Table 1).

\textbf{Baseline echocardiographic parameters}

Echocardiographic parameters at baseline for the entire cohort are
presented in Table 2. Mean LVEF was 64.3 +- 6.2 \% and 29 patients (18\%)
had valvular disease \selectlanguage{english}[?] moderate (n=5 aortic regurgitation, n=6 mitral
regurgitation, n=23 tricuspid regurgitation, n=1 aortic stenosis). As a
parameter of discrete upper septal thickening, the B-M ratio and ASA
were 1.28 +- 0.24 and 117.8 +- 13.9 degree (Table 2).

We found significant differences between patients with and without CTRCD
in LVEF (61.6 +- 5.3 \% vs. 65.0 +- 6.2 \%, P = 0.003), GLS (18.7 +- 2.9 \%
vs. 20.3 +- 3.4 \%, P = 0.008), LV mass index (LVMi) (101.1 +- 18.5
g/m\textsuperscript{2} vs. 92.8 +- 23.1 g/m\textsuperscript{2}, P =
0.047), B-M ratio (1.35 +- 0.22 vs. 1.26 +- 0.24, P = 0.029), and ASA
(112.1 +- 14.2 degree vs. 119.4 +- 13.4 degree, P = 0.005).

\textbf{Risk factors for CTRCD}

In univariate Cox proportional hazard analyses, LVEF, GLS, LVMi, and ASA
were significantly associated with the primary endpoint in baseline
echocardiographic parameters. In regard to clinical baseline
characteristics, age, performance status \selectlanguage{english}[?] 2, and history of ischemic
heart disease were associated with the primary endpoint (Table 3). In
the multivariable Cox proportional hazard analysis 1, GLS (HR per 1\%
decrease 1.19, 95\% CI 1.06-1.33, P = 0.003) and ASA (HR per 1 degree
increase 0.97, 95\% CI 0.95-0.99, P = 0.004) were identified as
independent risk factors. The multivariable analysis 2 clarified GLS (HR
per 1\% decrease 1.20, 95\% CI 1.07-1.35, P = 0.002), ASA (HR per 1
degree increase 0.97, 95\% CI 0.95-0.99, P = 0.003) and the history of
ischemic heart disease (HR 5.13, 95\% CI 1.94-13.56, P = 0.001) as the
independent risk factors for the primary endpoint (Table 3).

ROC curves for GLS and ASA regarding the incidence of CTRCD are
presented in Figure S1. Cut-off values were -19.4 \% for GLS, and 117
degree for ASA. The AUC, sensitivity, and specificity at each cut-off
value were 0.65, 0.61, and 0.63 for GLS; 0.67, 0.72, and 0.61 for ASA,
respectively (Figure S1). The Kaplan-Meier estimate curves for GLS and
ASA are shown in Figure 3, with significant differences observed between
each cut-off value.

\textbf{Incremental value of newly recognized risk factor}

According to the independent risk factors for CTRCD in this study, we
defined model 1 as consistent with a history of ischemic heart disease
and GLS, and model 2 as consistent with a history of ischemic heart
disease, GLS, and ASA. ROC curves for probability in model 1 and model 2
are presented in Figure 4. The C-statistic (AUC) for model 2 was 0.72,
which is superior to the 0.67 of model 1. The NRI and IDI were
calculated between model 1 and model 2. The reclassification table for
developing CTRCD is presented in Table 4, with a probability cut-off of
0.5. The NRI was (1 of 36 -- 0 of 36) -- (2 of 131 -- 0 of 131) = 0.028
-- 0.015 = 0.013 (95\% CI -0.004-0.029; P = 0.95), and the IDI was
(0.323 -- 0.293) -- (0.186 -- 0.194) = 0.030 + 0.008 = 0.038 (95\% CI
0.009-0.068; P = 0.017).

\textbf{DISCUSSION}

The current study demonstrated that ASA was the independent risk factor
for CTRCD in patients with ML who received the CHOP-like regimen, and
ASA had a significant incremental value to predict the development of
CTRCD. Any other clinical characteristics at baseline and dose of
anthracycline were not independent risk factors for CTRCD. Furthermore,
when excluding patients with valvular diseases \textgreater{} moderate
from the analyses, ASA was still an independent risk factor for
developing CTRCD (Table S2).

The relationship of almost all of echocardiographic parameters, except
LVEF and GLS, and CTRCD has not been examined previously. To the best of
our knowledge, this investigation is the first study to detect the
impact of morphological parameters in echocardiography on CTRCD. In our
study, history of ischemic heart disease and lower GLS were risk factors
for CTRCD, consistent with previous
studies\textsuperscript{11,15,22,23}. We also found that smaller ASA was
the new risk factor for CTRCD.

\textbf{Smaller ASA / ventricular sigmoid septum}

Several terms have been used to describe the sigmoid septum, including
discrete upper septal thickening (DUST), subaortic ventricular septal
bulge, and discrete upper septal knuckle. In general, the sigmoid septum
is frequently observed in the elderly population\textsuperscript{24-26},
although some investigators have reported this geometric change as part
of the spectrum of hypertrophic cardiomyopathy, because of LV outlet
obstruction \textsuperscript{27-29}. Therefore, the sigmoid septum is
considered to be the result of aging-related changes associated with
aortic atherosclerosis or thickening and calcification of the aortic or
mitral valve. \textsuperscript{30,31} In the current study, higher age
and higher body mass index were independently associated with the
presence of sigmoid septum, as defined by the cut-off value of the ROC
curve for CTRCD, in the logistic regression analysis (Table S3A). In the
current study, in univariable Cox regression analysis, age was one of
the significantly associated factors with CTRCD, consistent with
previous reports. However, after multivariable analysis, ASA was proven
as the independent risk factor for CTRCD, while age was not the
independent determinant. That seemed to be why morphologic change as a
result of aging was more specific and important for developing CTRCD
than aging itself.

The clinical and prognostic significance of the sigmoid septum has not
been clarified previously. A large prospective observational trial could
not show the effects of the sigmoid septum on exercise capacity in a
healthy population. \textsuperscript{32} In addition, a large
retrospective study reported that the sigmoid septum was not
independently associated with adverse clinical
outcomes.\textsuperscript{33} However, the criteria for the sigmoid
septum in these previous studies were based on the B-M ratio, which is
rather a representative parameter of DUST. One of the reasons why the
sigmoid septum had a clinically significant meaning in our study was the
use of ASA for the quantification of the sigmoid septum. In the previous
study, ASA was found to be the independent predictor of LV diastolic
dysfunction quantified by LV peak diastolic longitudinal strain rate in
healthy older subjects, otherwhile, age was not independently associated
with LV diastolic dysfunction. \textsuperscript{17} We anticipate ASA
could be an early predictor for LV dysfunction, resulting in being a
risk factor for CTRCD.

\textbf{GLS and a history of ischemic heart disease}

Lower LVEF and smaller GLS in patients with normal LVEF were already
recognized as risk factors for anthracycline-induced
CTRCD.\textsuperscript{11,13,14,18} In the current study, LVEF was not
an independent determinant for anthracycline-induced CTRCD in the
multivariable analysis, probably because GLS can detect myocardial
injury more sensitively than LVEF. \textsuperscript{34,35} History of
ischemic heart disease is also considered a risk factor for
CTRCD.\textsuperscript{23} Both decreased GLS and prior ischemic heart
disease at baseline are generally considered to be associated with LV
myocardial injury, even during LVEF is within normal limit. In the
logistic regression analysis for lower GLS below the cut-off value in
the current study, performance status \selectlanguage{english}[?] 2, higher total bilirubin and
lower LVEF were the independent determinants (Table S3B). Considering a
history of general risk factors of ischemic heart disease themselves
including hypertension, hyperlipidemia, diabetes mellitus, and smoking
were not identified as risk factors for CTRCD in this study, a history
of ischemic heart disease might indicate the myocardial damage more
directly.

\textbf{Possible theory for developing CTRCD}

Based on our main findings, echocardiography-proven lower LV
longitudinal contraction and LV morphological changes were independent
risk factors for CTRCD. These parameters are considered to progress
according to cumulative exposure to myocardial tissue damage, which may
be associated with several kinds of factors such as aging, obesity,
performance status, and liver function (Table S3). Furthermore, although
CTRCD defined by a decline in LVEF can recover to preserved LVEF by
medical treatments for heart failure \textsuperscript{11},
anthracycline-induced cardiomyocyte toxicity is pathologically
considered irreversible and cumulative. \textsuperscript{36} Taken these
mechanisms together, the frequency of anthracycline-induced CTRCD is
defined upon the accumulated myocardial tissue damage that is the sum of
the underlying myocardial damage before chemotherapy and additional
myocardial tissue injury by anthracycline. We can guess the degree of
myocardial tissue damage at baseline by lower GLS and the smaller ASA,
as the most relevant risk factors for anthracycline-induced CTRCD.

\textbf{Study limitations}

The current study has some limitations. First, it was a single-center,
retrospective study, and enrollment volume was limited. Second, a
relatively large number of patients who did not undergo baseline or
follow-up echocardiography were excluded. The differences between the
group who underwent analyses and the group who excluded because of the
absence of baseline or follow-up echocardiography are presented in Table
S4. Baseline age was higher in the analyzed group, suggesting the
attending physicians ordered echocardiographic examinations more
frequently to potentially high-risk patients, possibly resulting in the
high prevalence of CTRCD in the current study. Third, the timing of
follow-up echocardiography also varied depending on the attending
physician. The median interval duration between the follow-up
examinations was 112days, suggesting relatively well-quality follow-ups
were performed. However, there was a possibility that the diagnosis of
CTRCD was delayed or not be made. And fourth, the sensitivity and
specificity of cut-off values evaluated in the same cohort used for
derivation are biased due to over-optimism. Further study is needed to
assess the prognostic value of ASA in a prospective cohort.

\textbf{CONCLUSION}

In addition to lower GLS, decreased ASA was found to be a new
independent risk factor for anthracycline-induced CTRCD in patients with
ML who received a CHOP-like regimen.

\textbf{DECLARATIONS OF INTEREST}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{AUTHOR CONTRIBUTIONS}

Takafumi Nakayama and Yoshihiro Seo designed and performed the research.
Takafumi Nakayama wrote the paper, and Yoshihiro Seo oversaw the paper
and the whole research. Takafumi Nakayama, Yoshiko Oshima and Junki
Yamamoto collected the clinical data. Yasuhiro Shintani, Masashi Yokoi,
Tsuyoshi Ito, Kazuaki Wakami, Shuichi Kitada, Toshihiko Goto, Shigeru
Kusumoto, Tomonori Sugiura, Shinsuke Iida and Yoshihiro Seo revised the
paper critically. All authors approved the submission of the paper of
final version.



\textbf{FIGURE LEGENDS}

Figure 1.

Study flow diagram of patients' enrollment.

Figure 2.

Representative echocardiographic images when morphological parameters
associated with the sigmoid septum were measured. Basal-mid ratio was
defined as the ratio of basal to mid interventricular septal diameter
(A), aorto-septal angle was defined as the angle between the
anterior-wall of the aorta and the ventricular septal surface (B).

Figure 3.

Kaplan-Meier curves for CTRCD. CTRCD-free survival was calculated
according to each cut-off value for GLS (A) and ASA (B) determined by
receiver operating characteristic curves. Event-free survival rates were
significantly lower in groups with lower GLS and smaller ASA.

Figure 4.

C-statistics for developing CTRCD. (A) Model 1 includes a history of
ischemic heart disease and GLS as already known risk factors. (B) Model
2 includes a history of ischemic heart disease, GLS, and incremental
variables of ASA. The AUC of models 1 and 2 were 0.67 and 0.72,
respectively.

Figure S1.

Receiver operating characteristic curves to determine the cut-off values
of GLS (A) and ASA (B) for Kaplan-Meier analyses. Areas under the curves
(AUCs) were 0.65 for GLS and 0.67 for ASA. Sensitivities/specificities
were 0.61/0.63 and 0.72/0.61 in GLS and ASA, respectively.

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