Figure 8 The decrease of the short
axis radial strain rate firstly appeared in the left ventricular
anterior wall, posterior wall and inferior wall, while the short axis
circumferential strain rate showed different decrease in each segment.
(n=10) A: The short axis radial strain rate of ant. free wall. B: The
short axis radial strain rate of lateral wall. C: The short axis radial
strain rate of posterior wall. D: The short axis radial strain rate of
inf. free wall. E: The short axis radial strain rate of post. septal
wall. F: The short axis radial strain rate of anterior septum. G: The
short axis circumferential strain rate of ant. free wall. H: The short
axis circumferential strain rate of lateral wall. I: The short axis
circumferential strain rate of posterior wall. J: The short axis
circumferential strain rate of ant. base. K: The short axis
circumferential strain rate of post. septal wall. L: The short axis
circumferential strain rate of anterior septum. 5-FU + BEV group:
5-fluorouracil + bevacizumab group.
Discussion
Since 1957, 5-fluorouracil has become one of the first members of
fluorouracil chemotherapy. Soon it become one of the most widely used
drugs for solid tumors, and has become the basic drug of FOLFOX
chemotherapy program. Then bevacizumab has improved the anti-tumor
program, and the effect of chemotherapy was more significant. But at the
same time, the use of them was not without risk. At present, the
reported incidence of cardiotoxicity caused by the use of 5-fluorouracil
and bevacizumab varies, and its damage mechanism was also diverse.
However, it was crucial to detect and diagnose the anti-tumor drug
cardiotoxicity in the early stage and adjust the chemotherapy program,
so as to prevent unnecessary morbidity and mortality. According to the
current definition of cardiotoxicity caused by antitumor drugs,
LVEF<50% or LVEF reduced by 10% compared with baseline are clinical
cardiotoxicity symptoms【6】. In this study, different
detection technologies were explored to early diagnosis cardiotoxicity
caused by antitumor drugs.
ECG, as the most basic and convenient technology for clinical detection
of cardiac function, has been widely used. In the detection of
chemotherapy induced cardiotoxicity, we showed a decrease in heart rate
and an extension of PR interval on the 7th day, suggesting that
5-fluorouracil and bevacizumab may affect the cardiac electrical
conduction system, hinder the conduction of electrocardiograph. And ST
segment elevation suggested that 5-fluorouracil and bevacizumab may
injure system of coronary circulation. However, there was no significant
difference in ECG between the two groups, which indicated that the
sensitivity of ECG in the detection of chemotherapy induced
cardiotoxicity was low. At the same time, many other heart diseases that
affect the coronary artery can also show similar ECG performance, so it
needs to be further evaluated with other detection
methods【7】.
In this study, the BNP of 5-fluorouracil + bevacizumab group mice had no
significant change at all time points, probably because the heart injury
was not very serious. But some literatures pointed out that the BNP was
normal or not increased in the heart injury, indicating the poor
prognosis. At the same time, the change of serum BNP content appeared
the time varies from 1 month to 12 months. And if there was no other
index support, BNP elevation alone can not diagnose cardiac
insufficiency【8】. As for myocardial histopathology,
compared with other detection techniques, although it was the gold
standard for the diagnosis of myocardial
condition【9】, the heart function of patients may
have been greatly reduced before the heart pathology changing. In this
study, the degree of mouse heart was less damaged, it was difficult for
conventional myocardial histopathology to change in a large range. And
it was not suitable used for early detection of cardiotoxicity because
of invasive.
The 18F-FDG mediated PET myocardial imaging can
directly show the metabolism of mouse heart. We showed the increase of
myocardial uptake on the 7th day after injection, suggesting that it may
be an early manifestation of chemotherapy induced cardiotoxicity. This
may be related to the decrease of mitochondrial oxidation and the
abnormal metabolism of glycolysis energy produced by increased lactic
acid, such metabolic recombination may cause the activity of hexokinase
the increase of 18F-FDG phosphorylation lead to the
retention of intracellular tracers【10】. At the same
time, on the 14th day after injection, PET myocardial imaging can detect
myocardial damage more sensitively than other detection techniques,
especially the damage of left ventricle inferior wall、posterior wall
and posterior interval. But compared with other detection techniques,
PET was more complicated and had radiation to human body. Some studies
have shown that the changes of myocardial glucose metabolism can be
detected early in the course of anthracycline treatment. Through the
detection of FDG intake, the cardiac glucose consumption gradually
increases or even reached a higher level during and after chemotherapy,
and the incidence of cardiac toxicity also
increases【11】. However, CT shows its disadvantage in
the detection of chemotherapy induced cardiotoxicity. Because most of
cardiotoxicity caused by antineoplastic drugs has functional changes
first, and structural changes occur later, the incidence is also low, so
CT can not detect cardiotoxicity in the early stage.
Conventional echocardiography, as an imaging method for cardiac
detection, has been recommended by oncology and cardiology guidelines as
the main screening technology for cardiotoxicity of antineoplastic drugs
because of its advantages such as low cost, wide application, no
ionizing radiation and high patient acceptance. It can not only judge
heart failure and left ventricular systolic dysfunction, but also
observe structural changes in the heart caused by cancer treatment. In
this study, the IVS, LVPW thickness, LVEF and LVFS gradually decreased,
and there were statistical differences on the 14th day. In addition, we
also evaluated left ventricular diastolic function. The MVA, MVE, e’ and
E/e’ did not change significantly within 14 days after injection. Only
MVE/A decreased on the 7th day, but there was no statistical difference.
Therefore, 5-fluorouracil and bevacizumab had little effect on left
ventricular diastolic function. So we showed that left ventricular
diastolic function cannot be used for early detection of cardiotoxicity
induced by 5-fluorouracil and bevacizumab. However, it has been reported
that the left ventricular diastolic function can change in the early
stage of predicting adriamycin induced
cardiotoxicity【12】, which may be related to the
injury mechanism of antitumor drugs.
What more, we confirmed that the decrease of speckle tracking
echocardiography was earlier than that of conventional echocardiography,
which could be a sign of the subsequent decrease of cardiac function.
Speckle tracking echocardiography was a good method to measure
myocardial movement, in which strain reflected the degree of myocardial
motion in a cardiac cycle, and strain rate was the rate of myocardial
systole and diastole. The advantage of strain and strain rate
measurement was that it can distinguish the movement of each myocardial
segment and analyze the abnormal myocardial movement irrelevant to
normal myocardial movement. The peak strain can reflect the myocardial
contraction function irrelevant to cardiac load【13】.
Therefore, the measurement of strain and strain rate can provide the
heart’s own collection Information about the shrink function. A number
of studies have indicated that GLS can detect left ventricular
dysfunction before LVEF decreases, and it is one of the independent
predictors of mortality in all cardiotoxicity【14】.
Currently, the guideline recommends - 15% as subclinical indicators of
left ventricular dysfunction【15】.
Compared with strain and strain rate, we found that the former can
detect the heart injury earlier. Among them, GLS first changed in
overall strain. On the 7th day after injection, when LVEF had not
changed significantly, GLS decreased with statistical difference, while
GRS and GCS decreased later than GLS. It has been reported that the
decrease of GLS may be related to the dose of chemotherapy or
radiotherapy【16】. However, there was no clear
research on why GLS was the earliest indicator of overall strain change.
In addition to focusing on the global strain, we found that the strain
of different segments of the left ventricle changed at different times.
The decrease of the longitudinal strain of the long axis first occurred
in the left ventricle apical segment. In the aspect of left ventricular
long axis radial strain, the posterior wall decreased earlier than the
interventricular septum. In the observation of left ventricular short
axis strain, we found that the anterior wall of left ventricle decreased
first in both short axis radial strain and circumferential strain. It
can be seen that the area dominated by the anterior descending branch of
the left coronary artery may be more sensitive to the decrease of the
cardiac function in the strain index of the left ventricular short axis.
In conclusion, we showed that compared with other cardiac detection
techniques, speckle tracking echocardiography and18F-FDG myocardial imaging can detect myocardial
damage in early stage, but speckle tracking echocardiography is more
convenient. And GLS is the best indicator of cardiotoxicity in spot
tracking echocardiography. The decrease of the longitudinal strain of
the long axis of the left ventricle first occurred in the apical segment
of the left ventricle, the decrease of the radial strain of the long
axis of the left ventricle first occurred in the posterior wall of the
left ventricle, and the decrease of the radial strain and the
circumferential strain of the short axis of the left ventricle first
occurred in the anterior wall of the left ventricle.
In this study, we discussed the early detection of chemotherapy induced
cardiotoxicity by a variety of detection techniques. The chemotherapy
induced cardiotoxicity has a great influence on the expected survival
rate of patients. To control the adverse reactions of anti-tumor drugs
was important in clinical medication. Therefore, the establishment of
more effective early diagnosis methods to reduce or minimize
chemotherapy induced cardiotoxicity was desired. Fully understanding and
timely monitoring the cardiotoxicity of drugs was beneficial to the
prognosis of patients. In this way, we can provide the best treatment
plan for patients, and make anti-tumor drugs safer and more effective
for the benefit of cancer patients.