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.