Effects of Anthracyclines on Pericardial Adipose Tissue Assessed by Magnetic Resonance Imaging　― An Animal Experiment ―

Abstract

Background: Anthracyclines are widely used in cancer treatment, yet their potential for anthracycline-induced cardiotoxicity (AIC) limits their clinical utility. Despite the significant anatomical relevance of pericardial adipose tissue (PeAT) to cardiovascular disease, its response to anthracycline exposure remains poorly understood.

Methods and Results: Male New Zealand White rabbits (n=17) received weekly doxorubicin injections and underwent magnetic resonance imaging (MRI) scans biweekly for 10 weeks. PeAT volumes (total, left paraventricular, right paraventricular) were measured together with ventricular function. Histopathological evaluations were also conducted. A mixed linear model identified the earliest timeframe for detectable changes in PeAT volume and left ventricular function. Total PeAT volume decreased from the 6th week (1.17±0.06, P<0.05) and continued to decrease until the 8th week (0.96±0.06, P<0.05) and left paraventricular adipose tissue volume decreased significantly, but no changes were observed in right paraventricular adipose tissue volume. The volume of PeAT exhibited a positive correlation with left ventricular ejection fraction (LVEF) (r=0.43, P<0.05), which declined below 50% by the 8th week, and a negative correlation with myocardial cell injury scores (r=−0.595, P<0.05).

Conclusions: Anthracycline administration led to an early reduction in PeAT volume, particularly in the left paraventricular region, detectable by MRI as early as the 6th week. Changes in PeAT volume preceded alterations in LVEF and were associated with declines in cardiac function and myocardial cell damage.

Anthracyclines are one of the most effective anticancer drugs ever developed, and are widely used in the treatment of a variety of malignancies such as breast cancer, soft tissue sarcomas and aggressive lymphomas, acute lymphoblastic or myeloblastic leukemia.¹ However, their use has been limited by adverse effects in different organs, including the heart, brain, liver and kidneys, with the heart being the preferred target for anthracycline action.^2,3 Anthracycline-induced cardiotoxicity (AIC) will seriously affect the prognosis of patients, and some patients administered anthracyclines for anticancer treatment have died from cardiotoxicity in the later stages of drug therapy.^4,5 The commonly used clinical marker of AIC is left ventricular ejection fraction (LVEF),⁶ which has limitations for the early detection of AIC,^4,7 as well as left ventricular global longitudinal strain.^8,9

Pericardial adipose tissue (PeAT) envelops the heart, accounting for approximately 80% of its surface area and comprising between 20% and 50% of its mass.¹⁰ PeAT has 2 distinct layers: epicardial adipose tissue (EAT) and paracardial adipose tissue (PAT).^10–14 As a small adipose tissue reservoir, PeAT exhibits thermogenic and pro-inflammatory characteristics, and also has a protective role for the heart.^11–15 In patients with high-risk cardiac disease, PeAT can produce a variety of inflammatory mediators that exacerbate the local inflammatory response, with fibrosis occurring in the neighboring myocardium, which in turn can progress to heart failure.^14,16,17 Currently, several studies have reported that PeAT or EAT is associated with the risk of developing the toxic effects of anthracycline treatment,^13,18,19 and although its value for early detection of AIC is uncertain, this background indicates the potential for studying PeAT as an important non-invasive indicator of early cardiotoxicity.

Imaging techniques, particularly computed tomography (CT) and magnetic resonance imaging (MRI), are commonly used to quantify adipose tissue distribution,^20–22 but MRI appears to be the more appropriate imaging tool for assessing PeAT due to CT’s inherent drawback of exposure to ionizing radiation.²³ In particular, the steady-state free-precession (SSFP) sequence, which is currently the most accurate and reproducible tool available for assessing and calculating the volume of PeAT.^10,24

Recent studies investigating changes in PeAT volume after anthracycline treatment using MRI are limited; most studies have concentrated on the relationship between EAT and anthracyclines using imaging methods.^25–29 In addition to EAT, the PAT demonstrates a highly pro-inflammatory effect, which may potentially contribute to the pathogenesis of cardiovascular diseases.^14,30,31 Considering the entirety of the cardiac adipose tissue and its ease of delineation in imaging, assessing PeAT volume aligns better with clinical requirements for simplified procedures. Although a previous study did evaluate PeAT in patients using CT imaging,¹⁹ it lacked external validation and did not offer a dynamic explanation for the changes observed in PeAT during the onset and progression of AIC. Therefore, for the current study, we proposed an experiment with continuous injection of anthracyclines to dynamically monitor the changes of PeAT and LVEF by MRI, and to obtain the MRI diagnostic time point of early AIC occurrence, to provide new ideas and experimental bases for the clinical application of PeAT as a non-invasive monitoring index for early AIC.

Methods

Animal Model Preparation

All experiments were approved by the Institutional Review Board (approval no. SWMU20210384). Prior to the experiment, 20 New Zealand White rabbits were obtained and fed ad lib for 2 weeks to acclimatize. A baseline MRI scan was performed on all rabbits before the experiment. Random 3 rabbits were executed for the baseline histological assessment. The remaining 17 rabbits were weighed, and the dose of adriamycin was calculated based on the human dose recommended by the Chinese Society of Clinical Oncology (60 mg/m²) according to the conversion formula for human and animal body surface area. Doxorubicin (doxorubicin hydrochloride, Aladdin) was injected into the ear margins once a week, and MRI scans were performed every 2 weeks until the end of week 10. After each MRI scan, another 3 random rabbits were euthanased by overdose of inhaled isoflurane for histological evaluation. The rabbits were pacified and sedated during each scan and injection to prevent fear. Rabbits were excluded from analysis if (1) poor image quality or (2) baseline heart disease or myocardial injury. None of the rabbits fulfilled exclusion criterion (2).

MRI Scanning

Rabbits were weighed to calculate the drug dose, anesthetized by intramuscular injection of 2.0 mg/kg of isoproterenol (Meryer) into the lumbar muscles on both sides of the spine 1 h before each MRI scan and the anterior chest wall was shaved. The marginal ear veins of the rabbits were examined before injection of metoprolol hydrochloride (0.3 mg/kg). Isoproterenol was prepared temporarily under aseptic conditions using 5% dextran solution diluted 1 : 4 and had to be used within 6 h.

MRI scans were performed on a 1.5 T MRI scanner (Achieva, Philips Medical Systems, The Netherlands). PeAT and cardiac function parameters were analyzed with SSFP sequence images acquired on short-axis, 2-, 3- and 4-chamber long-axis views covering the entire left ventricle using the following parameters: repetition time (TR)=3.7 ms, echo time (TE)=1.84 ms, field of view=180×180 mm, matrix=144×144 pixels, reconstruction voxel size=1.25×1.25 mm², scout voxel size=1.25×1.25 mm², acquisition voxel size=1.67×1.67 mm², slice thickness=5 mm, and slice gap=1 mm.

Image Analysis

All images were evaluated using CVI42 (version 5.12.4, Circle Cardiovascular Imaging, Calgary, Canada) software by 2 radiologists with >3 years of experience in cardiac MRI diagnosis. The PeAT was manually outlined in the end-diastolic phase by selecting consecutive multilayered short-axis movie sequences. The innermost layer of the adipose tissue was outlined with the inner film tool, and the outermost layer of the adipose wall was outlined with the outer film tool, with the PeAT contour between the 2 layers. They manually adjusted the signal threshold slider and visually inspected to match the drawn adipose tissue with the high-signal fat in the image, to exclude non-adipose tissue areas (Figure 1). For the determination of PeAT volume, the area outlined by manual tracing was determined in each section and multiplied by the section thickness to derive the fat volume, and the total PeAT volume was obtained by summing the data from all sections.³² The left paraventricular adipose tissue (LPAT) and right paraventricular adipose tissue (RPAT) were demarcated in imaging analysis, using the right ventricular insertion points as anatomical boundaries.

Figure 1.

Images showing measurement of pericardial adipose tissue (PeAT) volume. The innermost layer of adipose tissue is outlined with a red line, the outermost layer of the fat wall is outlined with a blue line, and the yellow area between the two layers is PeAT.

According to Simpson’s method, left ventricular (LV) function was assessed on the 4- and 2-chamber long-axis views and the short-axis views of the cine MRI images. The end-diastolic volume (EDV), endsystolic volume (ESV), left ventricular ejection fraction (LVEF), cardiac output of the left ventricle, cardiac index (CI), left ventricular stroke volume (LVSV), heart rate (HR), and left ventricular mass/body surface area (Diast) were calculated.

Additionally, the same radiologist took a second measurement of all data sets 1 month later to determine the intra-observer variability. Interobserver variability was evaluated by these 2 independent and double-blinded observers.

Histological Analysis

Immediately after euthanasia of the rabbits, the heart was removed, a transverse section of the entire heart was taken in the middle of the heart along a horizontal plane and fixed in 10% formalin. After dehydration and injection, the sections were 5-μm thick and subjected to staining with hematoxylin-eosin and Sirius red staining for determining the collagen volume fraction (CVF%). A panoramic 250 digital slice scanner (3DHISTECH, Hungary) was used for imaging the sections. Histologic data were analyzed and evaluated by pathologists who were unaware of the MRI results. Ultrastructural features were characterized by myocardial fibrosis, cytoplasmic vacuolization, altered cardiomyocyte morphology etc.,^33,34 to ultimately score the myocardial injury to identify the presence of AIC.

Statistical Analysis

Statistical analysis was performed using IBM SPSS 26.0 software (IBM, Armonk, NY, USA). Normally distributed data are expressed as mean±standard deviation, while non-normally distributed continuous variables are expressed as median. P values less than 0.05 were statistically significant. Reproducible inter- and intra-observer variabilities were assessed using intragroup correlation coefficients (ICC), where ICC >0.75 represents high agreement, and subsequent statistics were performed. A linear mixed effects model was then used to assess the volume of PeAT at each time point and analyze the change trend in PeAT volume. Scatter plots were created, and linear correlation analysis was performed to assess whether there was any correlation between the volume of PeAT and LV function, myocardial cell injury score, and CVF.

Results

Clinical Data

The baseline and experimental modeling group information are given in Figure 2. After the 4th MRI scan, the 2 rabbits that died of accidental anesthetic overdose were included for the histological analysis. Due to the insufficient number of rabbits remaining, in the 6^th and 8^th weeks we reduced the number of pathological samples to two. Only 2 rabbits survived for 10 weeks and were not included in the statistical analysis. In addition, at baseline and in the 6^th week, 2 images, respectively, were excluded due to poor quality.

Figure 2.

Baseline and experimental information for each model group. Before the study began, 3 random rabbits were killed for histological baseline evaluation. At the 2^nd, 4^th, 6^th, and 8^th weeks, 3, 5, 2, and 2 rabbits, respectively, were killed for histological evaluation; the remaining rabbits continued until the 10^th week. At baseline and the 6^th week, 2 images, respectively, were excluded due to poor quality. Only 2 rabbits survived for 10 weeks and were not included in the statistical analysis. The 3 rabbits included in the experiment in the 6^th and 8^th weeks were not the same rabbits.

Characteristics of the Change in PeAT Volume

With increasing time, the rabbits’ weight decreased, showing statistical significance at the 4^th week (2.35±0.10, P<0.05), but there was no significant continued decrease in the next time periods (P>0.05). The volume of PeAT decreased from the 6^th week (1.17±0.06, P<0.05) and continued to decrease until the 8^th week (0.96±0.06, P<0.05). The volume of LPAT also declined from the 6^th week (0.50±0.07, P<0.05), but the decline in RPAT was not statistically significant during the observation period (P>0.05) (Table 1).

Table 1.

Volume Index of PeAT at Different Time Points

	Baseline (n=15)	Week 2 (n=14)	Week 4 (n=7)	Week 6 (n=3)	Week 8 (n=3)
PeAT Volume (mL)	1.52±0.04	1.41±0.04 (P=0.117)	1.41±0.05 (P=0.315)	1.17±0.06* (P<0.001)	0.96±0.06* (P<0.001)
LPAT Volume (mL)	0.74±0.04	0.75±0.04 (P=1.000)	0.71±0.05 (P=1.000)	0.50±0.07* (P=0.043)	0.49±0.07* (P=0.037)
RPAT Volume (mL)	0.75±0.03	0.70±0.04 (P=1.000)	0.76±0.05 (P=1.000)	0.60±0.08 (P=0.743)	0.57±0.08 (P=0.346)
Weight (kg)	2.66±0.09	2.62±0.09 (P=0.771)	2.35±0.10* (P=0.021)	2.71±0.15 (P=0.667)	2.39±0.14 (P=0.166)

Data are means±standard deviation. *P<0.05. LPAT, left paraventricular adipose tissue; PeAT, pericardial adipose tissue; RPAT, right paraventricular adipose tissue.

Correlation of PeAT Volume With LV Function and Pathological Evaluation

LVEF decreased statistically at the 8^th week (43±2%, P<0.05), and both the LVEDV and LVESV increased statistically at the 8^th week (P<0.05). The CI of the LV increased at the 6^th week (3.80±0.30, P<0.05) (Table 2).

Table 2.

Parameters of Left Ventricular Function at Different Time Points

	Baseline	Week 2	Week 4	Week 6	Week 8
LVEF	0.51±0.01	0.49±0.01 (P=1.000)	0.47±0.14 (P=0.244)	0.47±0.02 (P=1.000)	0.43±0.02* (P=0.005)
LVEDV (mL)	3.66±0.19	3.66±0.19 (P=1.000)	4.20±0.24 (P=0.740)	4.65±0.43 (P=0.358)	4.85±0.34* (P=0.027)
LVESV (mL)	1.79±0.10	1.87±0.10 (P=1.000)	2.20±0.13 (P=0.140)	2.46±0.27 (P=0.114)	2.77±0.19* (P<0.001)
CI (L/min/m2)	2.10±0.16	2.41±0.16 (P=1.000)	2.78±0.21 (P=0.192)	3.80±0.30* (P<0.001)	2.81±0.27 (P=0.367)
LVSV (mL)	1.81±0.10	1.78±0.10 (P=1.000)	1.99±0.13 (P=1.000)	2.19±0.23 (P=1.000)	2.08±0.18 (P=1.000)
HR (beats/min)	165.98±7.54	191.42±7.56 (P=0.138)	190.29±9.70 (P=0.431)	199.78±16.89 (P=0.690)	168.70±13.36 (P=1.000)

Data are mean±standard deviation. *P<0.05. CI, cardiac index; HR, heart rate; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular endsystolic volume; LVSV, left ventricular stroke volume.

PeAT showed a positive correlation with LVEF (r=0.43, P<0.05) and a negative correlation with LVESV (r=−0.38, P<0.05) (Figure 3); the LPAT and RPAT volumes were not related to any LV functional parameters (P>0.05). Furthermore, PeAT exhibited a negative correlation with the myocardial cell injury score (r=−0.595, P<0.05), but neither LPAT nor RPAT demonstrated a significant association with the myocardial cell injury score. Additionally, no correlation was identified between PeAT, LPAT, or RPAT and CVF (P>0.05).

Figure 3.

Scatter plots of the correlation analysis of PeAT with LVEF and LVESV revealed a positive correlation between PeAT and LVEF and a negative correlation between PeAT and LVESV. ESV, endsystolic volume; LV, left ventricular; LVEF, LV ejection fraction; PeAT, pericardial adipose tissue.

Pathological Findings

The initial baseline group had normal heart tissue with well-aligned myocardial fibers and no degenerative necrosis (Figure 4A), with a myocardial cell injury score of 0. After 2 weeks of chemotherapy, cytoplasmic vacuolization and myocardial fiber degeneration were found in the LV free wall (Figure 4B), with an average myocardial cell injury score of 0.2, which was in line with previous findings on cardiotoxicity.³³ After 6 weeks of chemotherapy, myocardial fibers in the lateral and septal wall of both ventricles were degenerated, and the cytoplasm contained vacuoles of varying sizes, and a small number of lymphocyte aggregates could be seen in the interstitium in some areas (Figure 4C), with an average myocardial cell injury score of one. As the study time progressed, pathological changes such as myocardial fiber degeneration and necrosis, inflammatory cell infiltration and other pathological changes could gradually be seen in the myocardial tissues, and myocardial damage intensified.

Figure 4.

Histologic images of left ventricular cardiomyocyte damage. (A) Normal myocardial tissue from baseline control rabbit. (B) Myocardial tissue after 2 weeks, showing a small amount of fibrosis. (C) Cardiac tissue after 6 weeks of chemotherapy, with cytoplasm containing vacuoles of variable size (green arrows). (HE; ×200).

Discussion

Main Findings

We observed a correlation among a reduction in PeAT volume, cardiomyocyte damage, and a decrease in LVEF through continuous monitoring of AIC development. Anthracyclines induced a decrease in PeAT volume as early as the 6^th week, detectable on MRI. Although the reduction in PeAT volume occurred subsequent to pathological damage to cardiomyocytes, it preceded conventional clinical biomarkers of AIC, such as LVEF. Furthermore, considering the relationship between decreased PeAT and both myocardial damage and decreased LVEF, a reduction in PeAT during anthracycline treatment should raise concerns for decreased systolic function, especially the potential clinical onset of AIC, particularly around the critical time point of the 6^th week, when MRI screening for cardiotoxicity may be warranted. This finding underscores the significance in clinical practice of monitoring PeAT volume for diagnosing cardiotoxicity. Additionally, LPAT more closely aligned with the trend of total PeAT. LPAT volume began to decrease as early as the 6^th week and continued to decrease thereafter, indicating that LPAT may be more sensitive to anthracycline treatment.

Anthracycline-Induced Reduction of PeAT Volume

In our animal model, a sustained reduction in PeAT was observed, which was consistent with several studies^35–38 that have documented a decrease in EAT volume in patients with heart failure and reduced EF (HFrEF). In the context of HFrEF, diminished EAT values correlate with myocardial injury, cardiac remodeling, and impaired LV systolic function.³⁹ This suggests a reduced capacity of EAT to buffer excess free fatty acids and fulfill the heart’s specific energy requirements. Furthermore, with regard to EAT, which envelops the coronary artery and is deemed a type of perivascular adipose tissue, any diminution in its volume is liable to precipitate a downturn in the synthesis of adiponectin,³⁵ a protein with a protective function during ischemic states and possessing the attributes of brown fat, as well as NRG4,⁴⁰ a component of the NRG protein family, which potentially has a protective function regarding blood vessels and the heart. Consequently, a diminution of PeAT (encompassing EAT) might attenuate this protective efficacy and subsequently affect cardiac health. By the 8^th week of our study, both LVEDV and LVESV had increased, indicating LV dilation, with adjacent EAT being compressed and a further reduction in PeAT volume being observed. However, some studies^19,26 have found that the EAT or PeAT volume increases following anthracycline chemotherapy. One study proposed that the increased EAT volume might have a protective role against LVEF decline and cardiac remodeling during anthracycline-based chemotherapy,²⁶ which indirectly aligns with our findings, because the decreased LVEF was associated with a reduction in PeAT volume, ultimately leading to clinical AIC (defined as LVEF <50%). The other study attributed the increase in PeAT to factors such as increased caloric intake and reduced physical activity in patients.¹⁹ Notably, our experimental results indicated that PeAT volume was not influenced by weight changes in the rabbits, as no change in PeAT volume was observed when weight was lost in the 4^th week. Importantly, none of the patients in that study²⁶ had an LVEF <50%, indicating no clinical onset of AIC, which limits the applicability of those findings to our study. Additionally, a study⁴¹ included various anthracycline agents, which may elicit different effects on adipocytes, whereas we specifically utilized only doxorubicin. These differences may account for the varied responses, as increases in EAT or PeAT could be associated with cardioprotective effects or tolerance to anthracyclines, whereas reductions in EAT/PeAT seem to correlate with decompensation and deterioration of LVEF.

Additionally, our study identified a correlation between LPAT volume and PeAT volume, while RPAT volume remained relatively stable. This discrepancy may stem from the primary effect of anthracyclines on the LV myocardium (notably as early as the 2^nd week in our study) with less pronounced effects on the right ventricular myocardium. The bidirectional regulatory relationship between the injured LV and LPAT results in LPAT changes closely mirroring overall PeAT volumetric changes. However, we did not observe a correlation between LPAT volume changes and LVEF in our experiments. This lack of correlation may be attributed to the process linking PeAT volume reduction to LVEF decrease being complex and requiring more time to investigate. Future studies need to explore this relationship.

Value of PeAT as an Early Non-Invasive Biomarker for AIC

At the 8^th week of consecutive anthracycline injections, a significant decrease in the LVEF value was observed, dropping to <50%. This observation is consistent with a diagnosis of cardiotoxicity and suggests that alterations in LVEF occur after those in PeAT. This underscores the potential utility of PeAT as an early, non-invasive biomarker that can be readily monitored, rendering it a valuable asset in clinical practice for the detection of initial cardiotoxicity signs prior to resorting to more invasive procedures or LVEF assessments. Furthermore, this delay could be associated with the positive correlation observed between the reduction in PeAT volume and the decrease in LVEF, as well as the negative correlation between the reduction of PeAT and the myocardial cell damage score. As anthracyclines primarily target myocardial cells, cardiotoxicity is initially and most prominently manifested in these cells, with pathological results showing damaged cardiomyocytes characterized by vacuolization or inflammatory cell infiltration by the 2^nd week. Additionally, anthracyclines may induce PeAT to secrete various factors that can influence cardiac structure and exacerbate myocardial cell damage.⁴² In response to heightened myocardial oxidative stress, stress signals emitted by cardiomyocytes, such as 4-hydroxynonenal and other potential agents, may initiate lipolysis in the PeAT. This process may be mediated through the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and the binding of natriuretic peptides to receptors that are highly expressed in adipose tissue, leading to a reduction in PeAT size,³⁵ and may be also due to increased energy consumption associated with myocardial cell damage.⁴³ In the 2^nd week, we observed no change in PeAT volume compared with baseline volume, possibly attributable to mild myocardial injury, as indicated by our pathological results, with significant changes in PeAT volume occurring after the transition to a decompensated phase. Consequently, PeAT changes lag those in cardiomyocytes, and early-stage myocardial injury may be reversible. Additionally, pathological assessment of cardiomyocyte damage presents significant challenges and is highly invasive in humans.

Continuous administration of anthracyclines results in progression of myocardial injury, evolving from mild compensatory damage to severe decompensated injury. Consequently, the heart’s capacity to buffer excessive free fatty acids diminishes, and its adaptability to meet specific energy demands is compromised.³⁹ A reduction in PeAT may lead to decreased production of adiponectin, a protein recognized for its protective effects, which resemble those of brown adipose tissue under ischemic conditions.³⁵ As myocardial injury intensifies and PeAT volume contracts, the activation of the cardiac renin-angiotensin system, activin A, and angiopoietin-2 by EAT products,^44,45 along with the secretion of inflammatory cytokines, lipid peroxides, altered fatty acid profiles, and other bioactive molecules by PAT^46,47 may complicate the study of the pathogenesis of cardiac dysfunction, characterized by decreased LVEF and cardiac fibrosis. Moreover, PAT products are pivotal regulators of mitochondrial function in the heart,⁴⁷ potentially associated with AIC. Hence, PeAT volume positively correlated with LVEF. Clinically, a decrease in PeAT volume should raise concerns about reduced systolic function, especially the potential onset of AIC.

It is crucial to acknowledge that these findings were derived from an animal experiment and thus serve as a preliminary reference for future non-invasive screening and follow-up studies in clinical patients using MRI to detect cardiotoxicity at an early stage. However, the extrapolation of these results to human patients necessitates further investigation. Furthermore, by concentrating on the volume reduction of PeAT through non-invasive imaging techniques, clinicians may detect cardiotoxicity at an earlier stage, thereby facilitating timely intervention and management in patients undergoing anthracycline therapy.

Study Limitations

First, the sample size in this animal model was small, but had continuous control observation of 5 time points, so the number was greatly increased, and we will expand the sample size in the subsequent study. Second, this experiment did not have a placebo control group, because we used the animals as their own before and after control, to avoid errors caused by individual differences. Third, the observation period of the experiment was short, only 10 weeks, because we mainly wanted to observe the early changes of AIC, and we will extend the period of observation in future studies. In addition, because of the small volume of PeAT with a relative big weighting error, and there being no fascia separating the EAT from the myocardium, we did not perform pathological sampling of the PeAT and inflammatory cytokines; However, the accuracy and reproducibility of MRI measurements of the PeAT have been verified.¹⁰ Ultimately, although this experiment was conducted in animals, we plan to collect MRI data from patients undergoing anthracycline-based chemotherapy. Our focus will be on determining the optimal timing for MRI screening, analyzing the characteristic changes of PeAT, and assessing its relationship with LVEF.

Conclusions

The volume of PeAT could decrease during chemotherapy withanthracycline, and was observed as early as the 6^th model week by MRI. Although the decrease in PeAT occurred later than the pathological changes of AIC, which appeared in the 2^nd week after anthracycline injection, it preceded the decline in LVEF. Furthermore, the reduction in PeAT correlated with both myocardial cell injury score and LVEF. This correlation implies that diminished PeAT volume is linked to myocardial damage and impairment of ventricular systolic function. Consequently, a decrease in PeAT during anthracycline chemotherapy may prompt concerns regarding the potential decline in systolic function, particularly at the pivotal time point around the 6^th week. At this juncture, MRI screening may be essential for the early detection of cardiotoxicity and the possible onset of AIC.

Acknowledgments

This research was partly supported by the joint program of Luzhou city and Southwest Medical University (2021LZXNYD-J20) and Sichuan Science and Technology Program (2024NSFSC1793).

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

There are no conflicts of interest. This research was partly supported by a joint program of Luzhou city and Southwest Medical University (2021LZXNYD-J20) and Sichuan Science and Technology Program (2024NSFSC1793).

The study complied with ethical standards and adhered to the Guidelines for Ethical Review of Laboratory Animal Welfare (GB/T 35892-2018, China). All procedures were approved by the Animal Ethics Committee of The Affiliated Hospital of Southwest Medical University (Approval No. SWMU20210384).

All authors have seen the manuscript and approved it for submission. Neither the entire paper nor any part of its content has been published or has been accepted elsewhere. It is not being submitted to any other journal. All are in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data Availability

The deidentified participant data will not be shared.

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