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\begin{document}

\title{Using 2D and 3D strain to detect myocardial damage during anthracycline
chemotherapy in breast cancer patients}



\author[1]{Fang-Yi Tao}%
\author[1]{Yin-Li Luo}%
\author[1]{Jing-Hong Xu}%
\author[1]{Shu-Ting Zhu}%
\author[1]{Bin-Bin Shi}%
\author[1]{Zeng-Hui Liang}%
\author[1]{Bin Chen}%
\affil[1]{The First Affiliated Hospital of Wenzhou Medical University}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
Both two-dimensional (2D) and three-dimensional (3D) echocardiography
can be used in the early diagnosis of myocardial toxicity in patients
with anthracycline chemotherapy. However, there are few studies on the
detection of early myocardial damage in specific regions. This study
compared the role and significance of 2D strain and 3D strain in
discovering early segmental dysfunction. We prospectively studied 56
breast cancer patients who received anthracycline therapy. The mean age
of patients was 47.6 \selectlanguage{ngerman}± 8.1 years. They all received 4-6 cycles of
chemotherapy. Before chemotherapy and after every two cycles, patients
underwent standard echo, 2D and 3D speckle-tracking echocardiography
(STE) and real-time three-dimensional echocardiography (RT-3DE).
Compared with the baseline value (T0), 3D GLS was significantly reduced
after two cycles (T2) (P\textless{}0.05), after four cycles (T4) 3D GCS
was significantly reduced (P\textless{}0.05), after six cycles (T6) 2D
derived EF, 2D GLS, E/e' ratio, Fractional shortening (FS), 3D derived
EF, 3D GAS, GRS were considerably decreased (P\textless{}0.05). The area
supplying blood from the anterior descending branch of the left coronary
artery was the most susceptible to chemotherapy, and 3D GLS was found
earlier than 2D GLS which was decreased considerably after two cycles
(P\textless{}0.05). In anthracycline chemotherapy patients, some regions
of early myocardial dysfunction may be more easily involved, through the
evaluation of 2D and 3D echocardiography, 3D speckle tracking
echocardiography may be more able to identify the involved segments of
myocardium early. Moreover, the apical segments of the left ventricle
seem to be more susceptible to cardiotoxicity.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

The survival rate of cancer patients has been significantly improved in
recent decades. Because of the development of early diagnosis
techniques, improved in the level of treatment and the implementation of
multidisciplinary treatment of cancer, and advances in adjuvant
chemotherapy and radiotherapy{[}1{]}. Although with the development of
anti-tumor drug therapy towards the direction of individual and targeted
therapy, its toxic and side effects should not be ignored. Research has
shown that about half of cancer deaths are caused by non-cancer causes,
and cardiovascular disease plays an important role{[}2{]}.

Anthracyclines are secondary metabolites produced by Streptomyces and
are one of the most effective anticancer drugs at present. It mainly
includes daunorubicin, Adriamycin, epirubicin, pirarubicin, mitoxantrone
and so on. Although the field of cancer treatment has changed
dramatically in recent decades, anthracyclines remain the cornerstone of
modern chemotherapy regimens for many cancers{[}3, 4{]}. However, the
most severe adverse reaction of anthracyclines is the cardiotoxicity
caused by anthracyclines. Numerous trials have indicated that most of
the cardiotoxicity caused by anthracyclines are persistent and
non-reversing, especially the first use of anthracyclines easily cause
cardiac damage. Therefore, early detection of cardiac insufficiency can
implement cardiac protection strategies before late and potentially
irreversible changes in cardiac function{[}5, 6{]}.

Echocardiography is a well-known non-invasive technique for assessment
of cardiac systolic and diastolic function, and it is the most commonly
used method for early identification and evaluation of cardiotoxicity
caused by antineoplastic drugs. Left-ventricular ejection fraction
(LVEF) is the most frequently used index to evaluate left ventricular
systolic function by conventional echocardiography, and the decrease of
LVEF is related to heart failure. However, its sensitivity to early
identification of cardiotoxicity is still controversial{[}7{]}. The
cardiotoxicity induced by anthracyclines was mostly positively
correlated with the dose, and in China the dose of anthracycline in the
treatment of breast cancer is relatively low. Therefore, more sensitive
monitoring methods are needed to monitor the cardiotoxicity associated
with low-dose anthracyclines. In recent years, with the development of
echocardiography technology, 2D and 3D speckle-tracking
echocardiographic parameters have been proved to be able to detect
preclinical abnormalities reliably at an early stage {[}8-10{]}.
Standard echocardiography can detect abnormalities in the presence of
obvious clinical symptoms. In the preclinical state, strain imaging can
make up for its deficiency and is of great help in early diagnosis and
define prognosis.{[}11{]}.

However, because of the different distribution of myocardial fibres,
some areas of the myocardium may be more prone to dysfunction{[}12{]}.
This study aimed to compare the role and significance of 2D strain and
3D strain in the detection of early segmental dysfunction, and to
explore which is more meaningful, including 3D global strain,
longitudinal strain, radial strain and circumferential strain.

\textbf{Materials and methods}

\textbf{Study population}

This prospective observational study screened more than 100 breast
cancer patients from April 2019 to May 2020 and plans to receive
anthracycline chemotherapy at the first affiliated Hospital of Wenzhou
Medical University. A detailed questionnaire was gathered, including the
presence of clinical history, electrocardiogram, an echocardiogram, and
blood sampling, at the recruitment. This study protocol was approved by
the Ethics Committee of the First Affiliated Hospital of Wen Zhou
Medical University.

Inclusion criteria were: at least 18 years of age; have not received
chemotherapy and (or) radiotherapy before; electrocardiogram (ECG),
kidney and liver function, blood routine tests were standard; breast
cancer was diagnosed by histopathology in our hospital, and at least
four cycles of chemotherapy were completed in our hospital.

Exclusion criteria were: pregnant or nursing women; metastatic breast
cancer; congenital heart disease; valvular disease; severe arrhythmia;
standard echo images of inadequate quality and echocardiographic
EF\textless{}50\% before chemotherapy.

The primary end-point was patients with significant LVEF decline without
congestive heart failure symptoms or mild symptoms (NYHA heart function
class I), LVEF decreased by at least 10\% and LVEF\textless{}53\%;
Patients with symptoms of congestive heart failure (NYHA heart function
grade II, III or IV grade), LVEF decreased by at least 5\% and
LVEF\textless{}53\%; GLS decreased by more than 15\% compared with the
baseline value before chemotherapy according to the ASE/EACVI Expert
Consensus{[}13-15{]}.

Finally, 56 patients met the criteria for enrollment. All patients will
be informed of the study aim and design and signed informed consent.
Each patient was then studied before chemotherapy, after the first
chemotherapy, and completion of anthracyclines therapy. The ATN dose,
heart rate, height and weight of the patients were recorded at the same
time of each study.

\textbf{Echocardiographic methods}

All transthoracic echocardiographic data were performed by a GE Vivid
E95 ultrasound machine (GE Healthcare, Oslo, Norway) with cardiac sector
probe M5S and 4V (1.0--1.5 Hz), and using Echopac workstation
(Version:201) for offline analyses. Connect the ECG to record the moving
image of at least five cardiac cycles (frame rate\textgreater{}40fps),
to ensure the image is clear (endocardium) and complete (including
epicardium), and adjust the frame rate to 40\% of the patient's heart
rate. All echocardiograms of each patient were obtained by the same
ultrasound machine.

\textbf{Standard ultrasoundexamination.}

Along the parasternal LV long-axis view measured the LV end-systolic
diameter (LVIDS), LV end-diastolic diameter (LVIDD), LV posterior wall
thickness (LVPW), end-systolic volume (ESV), end-diastolic volume (EDV).
LVEF as indicators to assess left ventricular systolic function was
calculated by the modified Simpson biplane method, with images recoded
from apical two-chamber and apical four-chamber views. Fractional
shortening (FS) was derived from M-mode imaging. In the apical
four-chamber section, the mean value of early diastolic peak velocity
(e') of septal and lateral mitral annulus was computed by tissue Doppler
and pulsed Doppler imaging. The E/e' ratio was calculated by the ratio
of the peak early transmission velocity (E) to the average e'. Then FS
and E/e' ratio could be used to evaluate left ventricular diastolic
function {[}16{]}. Moreover, we used M-mode and tissue Doppler imaging
echocardiography methods to measure isovolumic relaxation time (IRT),
isovolumic contraction time (ICT) and ejection time (ET), and then Tei
index((IRT+ICT)/ET) was computed automatically by the ultrasonic system
as a reliable estimate of left ventricular global function{[}17{]}.
These data were expressed as averages of three consecutive cycles.

\textbf{RT-3DE examination}

The 4V probe captured 3D full volume images in wide-angle mode when
holding the breath at the end of exhalation. Five fan-shaped images were
obtained through five consecutive cardiac cycles, and the volume ratio
of each sector image was set to about 40 Hz, which triggered ECG R wave
acquisition. Then, these datasets were stored and transferred to a
computer for offline analysis{[}18, 19{]}. The 3D datasets are displayed
as multiplanar reconstruction images, which correspond to apical 2- and
4-chamber views and three short-axis levels. And then though the
four-dimensional LV analysis software calculated LV end-systolic volume
(ESV), LV end-diastolic volume (EDV), LVEF and other parameters. (Figure
1)

\textbf{2D and 3D STE examination}

We used the same ultrasound machine to collect 2D and 3D
speckle-tracking images and stored all the datasets digitally in raw
data of this machine. The machine was equipped with the commercially
available software (4D Auto LVQ software, GE Healthcare) for online
quantification of 2D-derived GLS and 3D STE analysis. For 2D strain,
apical four-chamber, three-chamber and two-chamber images were
simultaneously collected by three-dimensional probe multi-plane mode in
the same cardiac cycle. For 3D strain, Image acquisition is the same as
real-time 3D full volume imaging. And then we could digitally send the
collected data to a separate workstation (EchoPAC PC, 201.1.1) for
subsequent offline analysis. The endocardial and epicardial border were
traced automatically, and the region of interest was determined by the
workstation. The machine automatically obtains 2D-STE and 3D-STE related
parameters of the left ventricle{[}10{]}. (Figure 2)

If there are any of the following situations in the image, they will be
excluded from the statistics: (1) the image quality is poor, and 3 of
the 17 segments of the left ventricular wall are rejected. (2) an
essential part of the left ventricular wall (\textgreater{} 25\%) is
outside the ultrasonic sector. (3) there is a volume rate lower than
40\% of the heart rate in the collected data. (4) the collection
contains ''suture'' artefacts or serious reverb artefacts{[}20, 21{]}.

\textbf{Statistical analysis.}

Data analysis was performed with SPSS 24.0 software.~All results were
expressed as means \selectlanguage{ngerman}± standard deviation (SD).~Data from two or more
repeated measurements were compared using an ANOVA.~The Pearson
correlation analysis was used for the analysis of continuous data.~All
reported p values were two-sided, and a P\textless{}0.05 was considered
an indication of statistical significance.

\textbf{Results}

In our study, 56 patients were enrolled, and two cases were excluded due
to poor image quality. All 54 patients completed anthracycline adjuvant
chemotherapy in our hospital. The patients were all women age from 29 to
69 years old, none of the patients had cardiac symptoms, and all
patients received dexrazoxane during the chemotherapy process. The
cumulative dose during chemotherapy was 483.5 ± 149.0 mg/m2. Three of
the 54 patients began radiotherapy after finished chemotherapy with
anthracyclines. The baseline characteristics of the study population are
presented in Table 1.

According to the standard 2D echocardiography evaluation: there were no
significant changes in the diametral lines of the heart during
chemotherapy; the LVEF values and FS values were significantly reduced
after six cycles (P\textless{}0.05), although there was a statistically
significant reduction in LVEF after anthracycline therapy, none of the
patients had heart-related symptoms. In the echo-Doppler parameters,
only the E/e\selectlanguage{english}' ratio (P\textless{}0.05) was significantly decreased after
six cycles, and there was no significant change in left ventricular
diastolic function parameters. Of note, representing the overall
function of the left ventricle TEI index also was decreased considerably
after six cycles (Table 2).

2D STE analyses are shown in Table 2, 3. Compared with the baseline
value, left ventricular global longitudinal strain (GLS) were reduced
significantly after two, four and six cycles (all p\textless{}0.05).
Moreover, the decreasing trend was more obvious with the increase of the
dose anthracycline (Table 2). We further discovered that after four
cycles the basal anterior segment (BA) and the apical septal segment
(AS) were altered significantly (all P\textless{}0.05); after six cycles
the basal anteroseptal segment (BAS) and apex segment were decreased
significantly (all P\textless{}0.05) (Table 2).

The 3D volumetric analyses are shown in Table 4. We found that EDV, ESV,
and LVEF were reduced significantly after six cycles compared to the
baseline values (all P\textless{}0.05), but all patients' LVEF was
within the normal range (LVEF\textgreater{}55\%).

3D STE analyses are shown in Table 4,5. We found that all 3D strain
parameters were significantly decreased after chemotherapy, GLS has
reduced dramatically after two cycles, especially. Additionally,
compared with baseline values, the basal anterior segment (BA), the
apical septal segment (AS) and the Apex segment were significantly
reduced after two cycles (all P \textless{} 0.05); the mid-anterior
segment (MA), the mid-anteroseptal segment (BAS) and the apical lateral
segment (AL) were altered significantly after six cycles (all P
\textless{} 0.05). (Figure 3)

\textbf{Discussion}

From this study, we tested the diagnostic value of 2D, 3D strain and 3D
volumetric analysis in detecting early changes of left ventricular
function in breast cancer patients who was undergoing anthracycline
chemotherapy. In particular, we further assessed and compared the global
and segmental longitudinal strains about the left ventricle derived from
2D strain and 3D strain.

The findings of the study indicated that: 1) on standard 2D
echocardiographic examination, with the cumulative doses of
anthracycline increased 2D derived EF decreased gradually and the E/e'
ratio representing left ventricular diastolic function increased
significantly; 2) on RT-3DE examination, the 3D volumetric parameters,
especially 3D derived EF can detect changes that cannot be seen by
two-dimensional echocardiography in time; 3) on 2D and 3D STE
examination, The subclinical changes of LV longitudinal function can be
found in the early stage of the course of the disease, whether it is the
GLS parameters derived from 2D strain or the GLS parameters derived from
the 3D strain. The difference is that 3D-derived GLS earlier, besides,
3D derived STE all the strain components decreased obviously with the
cumulative doses of anthracycline increased. 4) After anthracycline
chemotherapy, although the decrease degree of peak systolic strain in
each myocardial segment was different, the apical segments were found to
be the most vulnerable.

According to the time of occurrence, the myocardial damage caused by
anthracyclines can be listed as three categories: acute, chronic,
delayed cardiotoxicity. In most patients, cardiotoxicity can occur
quickly after anthracycline administration, and the damage is obvious
with the extension of time. The chronic and delayed cardiotoxicity of
anthracyclines were positively correlated with their cumulative
dose{[}22, 23{]}. Echocardiography and CMR have the advantage of
obtaining information on cardiac structure and function, and both can
avoid radiation exposure. More convenient and cheaper echocardiography
is the first choice for most patients during monitoring. Monitoring the
changes of LVEF is still the basis for the identification of
cardiotoxicity. From this study, we could find both 2D derived EF, and
3D derived EF decreased with the increased doses of
anthracycline{[}24{]}. And studies have proved that 3D derived EF and
CMR have similar accuracy{[}25{]}. However, compared with STE, it is not
sensitive to detect early myocardial damage, because a detectable
decrease in EF occurs only after a large amount of myocardial tissue is
lost, and this is consistent with recent research{[}26{]}.

Anthracycline-based cardiac toxicity induced by drugs is characterized
by myocardial cell death and irreversible cardiac injury. Because the
affinity of the anthracycline with myocardial tissue is significantly
higher than that of other tissues, so myocardial tissue is more likely
to be damaged. The early cardiotoxicity is characterized by
cardiomyocyte edema and degeneration, followed by cardiomyocytes
myolysis, sarcoplasmic reticulum distortion, replaced by fibrous tissue,
and even cardiomyocyte necrosis, resulting in heart failure. The basic
structure of myocardium is made up of circumferential fibres in the
mid-wall layer, the endocardial layers and epicardial layers are
composed of longitudinal and oblique muscle fibres{[}27{]}. In an
analysis by Crosby et al., researchers found that the absolute values of
the peak strain of ventricular septum contraction in each segment after
myocardial injury were different, and our results also confirmed
this{[}28{]}. According to the latest recommended by the American
college of cardiology section 17 section method, the left ventricular
segmental 17 bull 's-eye map blood supply distribution, the left
anterior item first-just branch (left anterior descending, LAD) supply
basal anterior(BA\selectlanguage{english}),basal anteroseptal(BAS), mid anterior(MA) , mid
anteroseptal(MAS), apical anterior(AA\selectlanguage{english}), apical septal(AS) , apex
section, right coronary (right coronary artery, RCA) supply basal
inferoseptal(BIS), basal lateral(BL), mid inferoseptal(MIS), mid
lateral(ML), apical inferior(AI) segment, and the left circumflex branch
(left circumflex artery, LCX) supply basal inferolateral(BIL), basal
anterolateral(BAL), mid inferolateral(MIL), mid anterolateral(MAL),
apical lateral(AL) segment{[}29{]}. From the findings of this study,
most of the descending segments belong to the blood supply region of the
left anterior descending branch, and the trend of the apical segments
were the most obvious. And 3D GLS was detected earlier than 2D GLS,
which is more meaningful for early detection. 3D-STE the motion of echo
spots from three-dimensional space by collecting real-time
three-dimensional images of the heart, so it can evaluate the motion of
the heart more accurately than 2D-STE.

\textbf{Limitations}

There are still many limitations to our research. Firstly, the sample
size of our study was not large enough, and the follow-up time was not
long enough to track the clinical event. But we follow up time was more
frequent could detect the early cardiac change in time. Secondly, 3D
echocardiography requires a clear and complete endocardial surface,
which requires high image quality, and the images we choose were
relatively clear and complete. In patients with left mastectomy, the
early data cannot be improved one week after the operation due to
incision and hematoma, and the late acoustic transparency is worse than
that of patients with right mastectomy. Therefore, the number of
patients with left mastectomy is small, and the selection of patients'
samples was relatively limited.

\textbf{Conclusion}

In summary, the study showed that using 2D GLS, RT-3DE, and 3D strain to
calculate GLS, GCS, GRS, GAS could detect earlier myocardial dysfunction
by chemotherapy. And the apical segments of the left ventricle seem to
be more susceptible to cardiotoxicity. This provides a new direction for
the study of anthracycline myocardial injury, for early myocardial
toxicity detection is more accurate to a certain myocardial segment,
more targeted timely and effective prevention and treatment.

\textbf{Acknowledgments}

The authors gratefully acknowledge the financial support by Wenzhou
Science and Technology Bureau, Grant No.{[}Y20190184{]}.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest.

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\par\null\par\null

\textbf{Figure 1} : Real-time 3D full volume data obtained by 4D
Automated LV Quantification software\selectlanguage{english}(4D Auto LVQ software, GE
Healthcare\selectlanguage{english}).(A4C: Apical four-chamber; A2C:Apical two-chamber; A3C:
Apical three-chamber; PSAX: Parasternal short-axis)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

A:The 4D Automated LV Quantification software traced the endocardial.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

B:The 4D Automated LV Quantification software traced the epicardial
border and obtained an entire delineation of the LV wall.

\textbf{Figure 2 LV's 17 segments bull's eye map and the relationship
between the coronary arteries}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3} : \textbf{The strain-time curve and 3D STE (bull's eye
depiction) in a patient during chemotherapy.}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

A: The strain-time curve and 3D STE (bull's eye depiction) at
baseline(T0).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

B: The strain-time curve and 3D STE (bull's eye depiction) after two
cycles (T2).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

C: The strain-time curve and 3D STE (bull's eye depiction) after six
cycles (T6).

\textbf{Table1 Clinical characteristics of participants at baseline}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Variable & Mean\selectlanguage{ngerman}±SD & Range\tabularnewline
\midrule
\endhead
Age (years) & 47.6\selectlanguage{ngerman}±8.1 & 29-68\tabularnewline
Body surface area (m2) & 1.6\selectlanguage{ngerman}±0.1 & 1.4-1.9\tabularnewline
Body mass index (kg/m2) & 24.0\selectlanguage{ngerman}±2.7 & 20.1-32.1\tabularnewline
Systolic blood pressure (mmHg) & 119.7\selectlanguage{ngerman}±10.8 & 91-144\tabularnewline
Diastolic blood pressure (mmHg) & 75.9\selectlanguage{ngerman}±8.2 & 65-96\tabularnewline
Heart rate (bpm) & 78.9\selectlanguage{ngerman}±8.7 & 60-100\tabularnewline
\bottomrule
\end{longtable}

SD, standard deviation.

\textbf{Table2 The 2D echocardiographic parameters during chemotherapy.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Variable & T0 & T1 & T2 & T4 & T6\tabularnewline
\midrule
\endhead
LVIDD (mm) & 44.73\selectlanguage{ngerman}±3.20 & 45.29\selectlanguage{ngerman}±3.21 & 45.75\selectlanguage{ngerman}±3.13 & 46.74\selectlanguage{ngerman}±2.99 &
47.10\selectlanguage{ngerman}±2.95\tabularnewline
LVIDS (mm) & 27.59\selectlanguage{ngerman}±2.35 & 28.25\selectlanguage{ngerman}±2.28 & 28.83\selectlanguage{ngerman}±2.26 & 29.52\selectlanguage{ngerman}±2.28 &
29.62\selectlanguage{ngerman}±2.14\tabularnewline
LVPW (mm) & 9.23\selectlanguage{ngerman}±0.52 & 9.32\selectlanguage{ngerman}±0.53 & 9.46\selectlanguage{ngerman}±0.51 & 9.66\selectlanguage{ngerman}±0.44 &
9.77\selectlanguage{ngerman}±0.38\tabularnewline
EDV (mL) & 91.18\selectlanguage{ngerman}±15.64 & 93.80\selectlanguage{ngerman}±15.23 & 95.86\selectlanguage{ngerman}±15.35 & 97.86\selectlanguage{ngerman}±14.63 &
97.63\selectlanguage{ngerman}±14.47\tabularnewline
ESV (mL) & 28.71\selectlanguage{ngerman}±6.18 & 30.12\selectlanguage{ngerman}±6.25 & 31.51\selectlanguage{ngerman}±5.97 & 32.98\selectlanguage{ngerman}±5.78 &
33.75\selectlanguage{ngerman}±5.97\tabularnewline
LVM/Ht (g/m2.7) & 37.95\selectlanguage{ngerman}±6.3 & 38.84\selectlanguage{ngerman}±6.08 & 39.29\selectlanguage{ngerman}±6.60 & 40.30\selectlanguage{ngerman}±6.54 &
41.56\selectlanguage{ngerman}±8.12\tabularnewline
EF (\%) & 68.61\selectlanguage{ngerman}±1.96 & 67.92\selectlanguage{ngerman}±2.04 & 65.82\selectlanguage{ngerman}±9.62 & 65.59\selectlanguage{ngerman}±1.96 &
63.59\selectlanguage{ngerman}±2.52\textsuperscript{a}\tabularnewline
FS (\%) & 38.25\selectlanguage{ngerman}±1.25 & 36.31\selectlanguage{ngerman}±5.42 & 36.12\selectlanguage{ngerman}±1.73 & 34.88\selectlanguage{ngerman}±7.31 &
34.84\selectlanguage{ngerman}±10.87 \textsuperscript{a}\tabularnewline
E/A ratio & 1.19\selectlanguage{ngerman}±0.37 & 1.19\selectlanguage{ngerman}±0.36 & 1.20\selectlanguage{ngerman}±0.34 & 1.19\selectlanguage{ngerman}±0.33 &
1.23\selectlanguage{ngerman}±0.42\tabularnewline
E velocity DT (ms) & 177.76\selectlanguage{ngerman}±10.09 & 163.33\selectlanguage{ngerman}±13.24 & 160.61\selectlanguage{ngerman}±11.03 &
151.84\selectlanguage{ngerman}±12.17 & 152.06\selectlanguage{ngerman}±14.50\tabularnewline
E/e' ratio & 9.01\selectlanguage{ngerman}±1.88 & 9.47\selectlanguage{ngerman}±1.90 & 9.08\selectlanguage{ngerman}±1.86 & 9.31\selectlanguage{ngerman}±2.03 & 9.40\selectlanguage{ngerman}±2.25
\textsuperscript{a}\tabularnewline
GLS & -21.86\selectlanguage{ngerman}±3.13 & -21.46\selectlanguage{ngerman}±2.84 & -19.69\selectlanguage{ngerman}±6.47 \textsuperscript{a} &
-19.04\selectlanguage{ngerman}±3.00 \textsuperscript{a} & -18.68\selectlanguage{ngerman}±3.27
\textsuperscript{a}\tabularnewline
TEI & 0.35\selectlanguage{ngerman}±0.03 & 0.35\selectlanguage{ngerman}±0.04 & 0.36\selectlanguage{ngerman}±0.04 & 0.38\selectlanguage{ngerman}±0.04 & 0.42\selectlanguage{ngerman}±0.04
\textsuperscript{a}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

LVIDD, left ventricular internal end-diastolic diameter; LVIDS, left
ventricular internal end-systolic diameter; LVPW, left ventricular
posterior wall thickness; EDV, end-diastolic volume; ESV, end-systolic
volume; LVM/Ht, left ventricular mass indexed for height; EF, ejection
fraction; DT, deceleration time; GLS, global longitudinal strain.

\textsuperscript{a} Compared with T0, \emph{P} \textless{} 0.05

\selectlanguage{english}\textbf{Table3 } \selectlanguage{english}\textbf{The 2D strain of 17 segments of the left
ventricular (x\emph{--}} \selectlanguage{ngerman}± s)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& T0 & T1 & T2 & T4 & T6\tabularnewline
\midrule
\endhead
BA (\%) & -21.35\selectlanguage{ngerman}±4.50 & -19.25\selectlanguage{ngerman}±4.61 & -17.98\selectlanguage{ngerman}±4.19 & -17.08\selectlanguage{ngerman}±3.75
\textsuperscript{a} & -15.67\selectlanguage{ngerman}±3.91 \textsuperscript{a}\tabularnewline
BAS (\%) & -17.24\selectlanguage{ngerman}±3.00 & -16.37\selectlanguage{ngerman}±3.19 & -16.56\selectlanguage{ngerman}±2.92 & -15.61\selectlanguage{ngerman}±3.97 &
-15.32\selectlanguage{ngerman}±3.15 \textsuperscript{a}\tabularnewline
BIS (\%) & -19.00\selectlanguage{ngerman}±3.09 & -17.63\selectlanguage{ngerman}±3.18 & -17.92\selectlanguage{ngerman}±3.71 & -17.12\selectlanguage{ngerman}±3.29 &
15.66\selectlanguage{ngerman}±4.75\tabularnewline
BL (\%) & -17.98\selectlanguage{ngerman}±3.14 & -17.65\selectlanguage{ngerman}±3.95 & -16.84\selectlanguage{ngerman}±5.54 & -16.63\selectlanguage{ngerman}±3.13 &
14.37\selectlanguage{ngerman}±6.63\tabularnewline
BIL (\%) & -16.65\selectlanguage{ngerman}±3.99 & -17.57\selectlanguage{ngerman}±3.82 & -17.02\selectlanguage{ngerman}±3.46 & -16.12\selectlanguage{ngerman}±4.45 &
-16.57\selectlanguage{ngerman}±3.40\tabularnewline
BAL (\%) & -15.53\selectlanguage{ngerman}±4.92 & -15.27\selectlanguage{ngerman}±4.40 & -14.58\selectlanguage{ngerman}±3.62 & -14.67\selectlanguage{ngerman}±4.12 &
-12.83\selectlanguage{ngerman}±4.96\tabularnewline
MA (\%) & -24.96\selectlanguage{ngerman}±5.43 & -22.16\selectlanguage{ngerman}±5.89 & -21.10\selectlanguage{ngerman}±4.38 & -19.78\selectlanguage{ngerman}±4.79 &
-17.51\selectlanguage{ngerman}±5.05\tabularnewline
MAS (\%) & -22.18\selectlanguage{ngerman}±3.13 & -21.24\selectlanguage{ngerman}±2.75 & -20.86\selectlanguage{ngerman}±2.67 & -19.98\selectlanguage{ngerman}±2.95 &
-18.88\selectlanguage{ngerman}±2.97\tabularnewline
MIS (\%) & -21.94\selectlanguage{ngerman}±3.97 & -21.31\selectlanguage{ngerman}±2.80 & -20.10\selectlanguage{ngerman}±7.03 & -19.63\selectlanguage{ngerman}±3.33 &
-17.90\selectlanguage{ngerman}±4.41\tabularnewline
ML (\%) & -21.41\selectlanguage{ngerman}±3.85 & -20.29\selectlanguage{ngerman}±3.86 & -19.98\selectlanguage{ngerman}±4.34 & -18.34\selectlanguage{ngerman}±3.41 &
-16.80\selectlanguage{ngerman}±4.13\tabularnewline
MIL (\%) & -19.98\selectlanguage{ngerman}±4.07 & -20.12\selectlanguage{ngerman}±3.49 & -18.78\selectlanguage{ngerman}±3.68 & -17.10\selectlanguage{ngerman}±4.45 &
-17.04\selectlanguage{ngerman}±3.36\tabularnewline
MAL (\%) & -20.57\selectlanguage{ngerman}±4.10 & -19.06\selectlanguage{ngerman}±5.45 & -18.10\selectlanguage{ngerman}±5.21 & -17.24\selectlanguage{ngerman}±3.92 &
-15.00\selectlanguage{ngerman}±7.19\tabularnewline
AA (\%) & -28.78\selectlanguage{ngerman}±4.74 & -26.78\selectlanguage{ngerman}±4.53 & -24.64\selectlanguage{ngerman}±4.5 & -23.57\selectlanguage{ngerman}±4.95 &
-21.57\selectlanguage{ngerman}±4.60\tabularnewline
AS (\%) & -28.57\selectlanguage{ngerman}±4.94 & -26.78\selectlanguage{ngerman}±4.62 & -25.20\selectlanguage{ngerman}±4.37 & -23.00\selectlanguage{ngerman}±4.95
\textsuperscript{a} & -20.63\selectlanguage{ngerman}±5.60 \textsuperscript{a}\tabularnewline
AI (\%) & -26.96\selectlanguage{ngerman}±4.82 & -25.37\selectlanguage{ngerman}±4.09 & -23.00\selectlanguage{ngerman}±5.03 & -21.29.6.96 &
-19.61\selectlanguage{ngerman}±5.13\tabularnewline
AL (\%) & -28.69\selectlanguage{ngerman}±5.56 & -26.08\selectlanguage{ngerman}±6.04 & -23.98\selectlanguage{ngerman}±6.5 & -21.86\selectlanguage{ngerman}±5.37 &
-18.59\selectlanguage{ngerman}±6.01\tabularnewline
Apex (\%) & -28.31\selectlanguage{ngerman}±4.50 & -26.22\selectlanguage{ngerman}±4.48 & -22.63\selectlanguage{ngerman}±4.40 & -22.63\selectlanguage{ngerman}±4.40 &
-20.30\selectlanguage{ngerman}±4.49 \textsuperscript{a}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textsuperscript{a} Compared with T0, \emph{P} \textless{} 0.05

\textbf{Table4 The 3D echocardiographic parameters during chemotherapy.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
Variable & T0 & T1 & T2 & T4 & T6\tabularnewline
\midrule
\endhead
EDV (mL) & 80.33\selectlanguage{ngerman}±15.54 & 84.78\selectlanguage{ngerman}±15.03 & 87.63\selectlanguage{ngerman}±14.73 & 89.20\selectlanguage{ngerman}±14.39 &
91.84\selectlanguage{ngerman}±14.11 \textsuperscript{a}\tabularnewline
ESV (mL) & 31.12\selectlanguage{ngerman}±7.09 & 33.76\selectlanguage{ngerman}±7.65 & 35.33\selectlanguage{ngerman}±7.55 & 36.90\selectlanguage{ngerman}±7.09 &
38.98\selectlanguage{ngerman}±7.59 \textsuperscript{a}\tabularnewline
SV (mL) & 49.71\selectlanguage{ngerman}±9.36 & 51.25\selectlanguage{ngerman}±9.32 & 52.55\selectlanguage{ngerman}±7.92 & 52.73\selectlanguage{ngerman}±8.67 &
54.31\selectlanguage{ngerman}±8.29\tabularnewline
CO (L/m) & 3.68\selectlanguage{ngerman}±0.76 & 3.89\selectlanguage{ngerman}±0.88 & 3.95\selectlanguage{ngerman}±0.79 & 4.01\selectlanguage{ngerman}±8.67 &
4.17\selectlanguage{ngerman}±0.74\tabularnewline
EF (\%) & 62.18\selectlanguage{ngerman}±2.86 & 60.84\selectlanguage{ngerman}±3.34 & 60.00\selectlanguage{ngerman}±3.11 & 59.16\selectlanguage{ngerman}±3.09 & 58.53\selectlanguage{ngerman}±4.15
\textsuperscript{a}\tabularnewline
SpI & 0.33\selectlanguage{ngerman}±0.07 & 0.34\selectlanguage{ngerman}±0.07 & 0.34\selectlanguage{ngerman}±0.08 & 0.34\selectlanguage{ngerman}±0.79 &
0.36\selectlanguage{ngerman}±0.07\tabularnewline
LVM/Ht (g/m2.7) & 41.82\selectlanguage{ngerman}±5.23 & 42.68\selectlanguage{ngerman}±4.57 & 43.71\selectlanguage{ngerman}±4.43 & 43.87\selectlanguage{ngerman}±5.40 &
44.71\selectlanguage{ngerman}±5.52\tabularnewline
GLS (\%) & -19.02\selectlanguage{ngerman}±3.25 & -17.84\selectlanguage{ngerman}±3.18 & -16.51\selectlanguage{ngerman}±3.06 \textsuperscript{a} &
-15.37\selectlanguage{ngerman}±2.83 \textsuperscript{a} & -14.02\selectlanguage{ngerman}±4.19
\textsuperscript{a}\tabularnewline
GCS (\%) & -17.76\selectlanguage{ngerman}±3.55 & -15.84\selectlanguage{ngerman}±3.47 & -15.20\selectlanguage{ngerman}±3.14 & -13.47\selectlanguage{ngerman}±3.18
\textsuperscript{a} & -10.92\selectlanguage{ngerman}±8.55 \textsuperscript{a}\tabularnewline
GAS (\%) & -31.18\selectlanguage{ngerman}±5.03 & -28.82\selectlanguage{ngerman}±4.94 & -27.06\selectlanguage{ngerman}±4.31 & -25.39\selectlanguage{ngerman}±4.42 &
-22.55\selectlanguage{ngerman}±5.93 \textsuperscript{a}\tabularnewline
GRS (\%) & 53.24\selectlanguage{ngerman}±12.90 & 46.98\selectlanguage{ngerman}±10.53 & 43.90\selectlanguage{ngerman}±10.23 & 39.02\selectlanguage{ngerman}±13.45 &
35.90\selectlanguage{ngerman}±8.52 \textsuperscript{a}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

SV, stroke volume; CO, cardiac output; GCS, global circumferential
strain; GAS, global area strain; GRS, global radial strain; SpI,
Sphericity Index

\textsuperscript{a} Compared with T0, \emph{P} \textless{} 0.05

\selectlanguage{english}\textbf{Table5 The 3D} \selectlanguage{english}\textbf{strain of 17 segments of the left
ventricle (x\emph{--}} \selectlanguage{ngerman}± s)\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& T0 & T1 & T2 & T4 & T6\tabularnewline
\midrule
\endhead
BA (\%) & -16.75\selectlanguage{ngerman}±6.10 & -14.75\selectlanguage{ngerman}±7.17 & -13.96\selectlanguage{ngerman}±5.54 \textsuperscript{a} &
-12.24\selectlanguage{ngerman}±8.04 \textsuperscript{a} & -11.60\selectlanguage{ngerman}±7.55
\textsuperscript{a}\tabularnewline
BAS (\%) & -17.86\selectlanguage{ngerman}±5.36 & -16.65\selectlanguage{ngerman}±4.08 & -15.69\selectlanguage{ngerman}±6.20 & -15.73\selectlanguage{ngerman}±4.83 &
-15.25\selectlanguage{ngerman}±5.12\tabularnewline
BIS (\%) & -26.84\selectlanguage{ngerman}±6.42 & -24.76\selectlanguage{ngerman}±6.56 & -22.86\selectlanguage{ngerman}±6.90 & -22.06\selectlanguage{ngerman}±5.90 &
-19.93\selectlanguage{ngerman}±8.29\tabularnewline
BL (\%) & -23.59\selectlanguage{ngerman}±9.51 & -23.51\selectlanguage{ngerman}±8.43 & -21.92\selectlanguage{ngerman}±7.42 & -19.50\selectlanguage{ngerman}±10.28 &
-15.00\selectlanguage{ngerman}±10.48\tabularnewline
BIL (\%) & -29.67\selectlanguage{ngerman}±9.02 & -26.76\selectlanguage{ngerman}±9.74 & -24.39\selectlanguage{ngerman}±11.14 & -21.94\selectlanguage{ngerman}±11.39 &
-19.17\selectlanguage{ngerman}±11.57\tabularnewline
BAL (\%) & -25.63\selectlanguage{ngerman}±8.44 & -23.10\selectlanguage{ngerman}±8.67 & -22.17\selectlanguage{ngerman}±8.64 & -20.64\selectlanguage{ngerman}±7.19 &
-18.88\selectlanguage{ngerman}±7.84\tabularnewline
MA (\%) & -16.84\selectlanguage{ngerman}±6.27 & -15.86\selectlanguage{ngerman}±6.19 & -13.63\selectlanguage{ngerman}±7.36 & -13.42\selectlanguage{ngerman}±5.75 &
-13.35\selectlanguage{ngerman}±6.16 \textsuperscript{a}\tabularnewline
MAS (\%) & -20.43\selectlanguage{ngerman}±3.47 & -19.31\selectlanguage{ngerman}±3.55 & -18.63\selectlanguage{ngerman}±4.23 & -17.94\selectlanguage{ngerman}±3.81 &
-17.29\selectlanguage{ngerman}±3.57 \textsuperscript{a}\tabularnewline
MIS (\%) & -22.37\selectlanguage{ngerman}±3.91 & -20.57\selectlanguage{ngerman}±4.02 & -20.85\selectlanguage{ngerman}±4.31 & -20.19\selectlanguage{ngerman}±4.18 &
-17.85\selectlanguage{ngerman}±5.68\tabularnewline
ML (\%) & -16.86\selectlanguage{ngerman}±8.23 & -14.74\selectlanguage{ngerman}±8.43 & -14.45\selectlanguage{ngerman}±8.73 & -13.52\selectlanguage{ngerman}±8.85 &
-11.02\selectlanguage{ngerman}±9.89\tabularnewline
MIL (\%) & -13.90\selectlanguage{ngerman}±9.28 & -12.88\selectlanguage{ngerman}±8.37 & -11.30\selectlanguage{ngerman}±8.71 & -9.95\selectlanguage{ngerman}±8.98 &
-6.06\selectlanguage{ngerman}±8.90\tabularnewline
MAL (\%) & -14.73\selectlanguage{ngerman}±8.00 & -11.86\selectlanguage{ngerman}±9.05 & -10.16\selectlanguage{ngerman}±7.87 & -10.44\selectlanguage{ngerman}±7.88 &
-8.60\selectlanguage{ngerman}±7.60\tabularnewline
AA (\%) & -18.58\selectlanguage{ngerman}±4.91 & -18.63\selectlanguage{ngerman}±4.16 & -16.10\selectlanguage{ngerman}±6.88 & -17.06\selectlanguage{ngerman}±4.63 &
-17.22\selectlanguage{ngerman}±4.74\tabularnewline
AS (\%) & -19.37\selectlanguage{ngerman}±5.79 & -17.06\selectlanguage{ngerman}±8.86 & -17.59\selectlanguage{ngerman}±5.13 \textsuperscript{a} &
-16.60\selectlanguage{ngerman}±5.02 & -14.50\selectlanguage{ngerman}±5.95 \textsuperscript{a}\tabularnewline
AI (\%) & -13.16\selectlanguage{ngerman}±6.76 & -12.45\selectlanguage{ngerman}±6.78 & -11.59\selectlanguage{ngerman}±6.90 & -10.24\selectlanguage{ngerman}±7.99 &
-8.42\selectlanguage{ngerman}±6.98\tabularnewline
AL (\%) & -13.61\selectlanguage{ngerman}±5.13 & -12.47\selectlanguage{ngerman}±6.68 & -12.25\selectlanguage{ngerman}±4.20 & -11.51\selectlanguage{ngerman}±4.04 &
-11.08\selectlanguage{ngerman}±5.38 \textsuperscript{a}\tabularnewline
Apex (\%) & -11.94\selectlanguage{ngerman}±6.64 & -10.76\selectlanguage{ngerman}±6.23 & -11.94\selectlanguage{ngerman}±6.64 \textsuperscript{a}
& -9.00\selectlanguage{ngerman}±6.79 \textsuperscript{a} & -8.52\selectlanguage{ngerman}±8.02
\textsuperscript{a}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{ngerman}

\textsuperscript{a} Compared with T0, \emph{P} \textless{} 0.05

\selectlanguage{english}
\FloatBarrier
\end{document}

