Improved methodology for establishing a mitral regurgitation animal model guided by intracardiac echocardiography

Introduction

Mitral regurgitation (MR), moderate or greater, was the most prevalent valvular disorder, with a population prevalence of 1.7%—approximately four times higher than that of aortic stenosis (AS; 0.4%). Notably, among individuals aged >75 years, MR prevalence can reach 9.3%, substantially exceeding the AS prevalence of 2.8%; the disease burden of MR is particularly pronounced due to its insidious progression and therapeutic challenges (1). Although cardiac surgery remains the first-line treatment for severe MR, nearly two-thirds of MR patients are ineligible for surgery due to factors such as poor cardiac function, multiple comorbidities, and advanced age (2). The currently low surgical treatment rate indicates significant potential for minimally invasive and safe treatment methods, such as interventional therapies. In recent years, transcatheter mitral valve interventions (TMVIs), have shown considerable progress (3). Mitral transcatheter edge-to-edge repair (M-TEER) has been used clinically as a safe and effective option for treating patients with severe MR (4). The highly promising market has attracted numerous startups to invest in the research and development of devices for the TMVI. MR animal models can be used to evaluate the long-term preclinical efficacy and safety of these devices (5,6). Furthermore, the MR model can also be utilized for studies related to hemodynamics and ventricular remodeling, contributing to the understanding of the pathophysiological mechanisms underlying the onset and progression of MR (7-9). Therefore, establishing a reproducible and stable MR model is crucial for exploring the pathogenesis and treatment strategies of MR.

Currently, creating large animal models of MR typically involves cutting off the mitral chordae using open-chest and transcatheter techniques (10). The traditional open-chest method is highly invasive, resulting in high mortality and complication rates, and the complex modeling process makes it difficult to replicate. Transcatheter methods, meanwhile, are minimally invasive, simple, and less traumatic; these models have high postoperative survival rates and are easier to replicate, facilitating the establishment of standardized models. Existing transcatheter methods are mainly guided by fluoroscopy, transesophageal echocardiography (TEE), or transthoracic echocardiography (TTE) (11-13). However, these imaging techniques fail to obtain sufficiently clear mitral chordae images in large ruminants, such as sheep and swine, frequently resulting in inadequate regurgitation (10).

Therefore, this study optimized the entire modeling process based on the transcatheter method, aiming to provide a more reliable and stable strategy for constructing large animal models of MR. We present this article in accordance with the ARRIVE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1782/rc).

Methods

Animal selection

Currently, sheep, swine, and canine are the primary large animal species used for establishing models of heart valve disease. For this study, we chose the Small-tailed Han sheep as the model organism for developing the MR model due to their docile nature and ease of management. Furthermore, the anatomy of the heart, valve size, and physiological parameters, such as heart rate and blood pressure, in adult sheep closely resemble those in humans (14,15). Additionally, their echocardiographic parameters fall within the normal range for humans (16). An essential feature is the slow growth rate of sheep, which prevents mismatches between the implanted valve and native tissue, a concern in rapidly growing species such as swine. This characteristic helps avoid issues such as paravalvular leakage during preclinical evaluation of interventional devices for heart valve. Therefore, sheep are unquestionably regarded as the most suitable models for researching heart valve diseases (17).

Pre-operative preparation

Our experiments were conducted using 12 Small-tailed Han sheep, all males, aged 16–22 months, and weighing 70–80 kg, which were provided by China Medical City (CMC) Large Animal Research Center (Jiangsu, China). The animals were housed in an animal facility of CMC [temperature: 16–28 ℃, relative humidity (RH): 40–70%, ventilation rate: ≥8 air changes per hour, lighting conditions: 12-hour light/12-hour dark cycle with full-spectrum daylight lamps] and provided with Municipal Water and Commercial Feed (Xietong Biology Co., Ltd., Jiangsu, China) ad libitum. A protocol was prepared before the study without registration. All animal experiments were performed under a project license (No. MFL-IACUC-2023-040V1.0) granted by the Institutional Animal Care and Use Committee of CMC Large Animal Research Center, in compliance with Chinese national Regulations on the Administration of Laboratory Animals. A week prior to surgery, a thorough cleaning and screening of the experimental animals was conducted. Animals exhibiting abnormal results in routine blood tests and biochemical tests were excluded. After obtaining 12-lead electrocardiograms (ePM 12M Vet, Mindray, Shenzhen, China), the recordings were analyzed to confirm sinus rhythm and exclude any arrhythmias or conduction abnormalities. TTE (EPIQ 7C; Philips Healthcare, Royal Philips Electronics, Amsterdam, The Netherlands) was performed to exclude structural heart disease in all experimental animals. Sheep that passed the screening and completed pre-operative preparation were included in the experimental group and assigned identification numbers. The subjects were randomly allocated to 2 groups using a random number table: Group TTE (n=6), which underwent modeling under TTE guidance, and Group ICE (n=6), which underwent modeling under intracardiac echocardiography (ICE) guidance. The weights of the animals in the 2 groups were 74.6±2.0 and 73.2±3.2 kg, respectively, with no intergroup difference observed (P=0.394). Each group comprised different echocardiographers and lead surgeons, all hailing from renowned medical institutions within China. These professionals had received specialized training and possessed extensive clinical experience. Prior to the procedures, they were instructed to terminate the surgery once the induced area of regurgitation reached a moderate level, and they adhered strictly to this directive.

Surgical procedure

The sheep was positioned in the right lateral position. Following general anesthesia and endotracheal intubation, induction of anesthesia is achieved using propofol (1.5–3 mg/kg), and maintenance was facilitated with isoflurane (1–6%). Echocardiography and electrocardiography were conducted, and the findings were documented. The left side of the neck was sterilized, and sterile drapes were applied. A longitudinal incision was made at the pulsatile site of the carotid artery to separate and expose both the carotid artery and jugular vein. Heparin was administered to maintain an activated clotting time (ACT) exceeding 300 s.

• ICE Group: an 11-Fr short guiding sheath (Check-Flo; Cook Medical, Bloomington, IN, USA) was inserted through the jugular vein puncture, while a 7-Fr short sheath (Check-Flo; Cook Medical) was inserted via the carotid artery puncture (Figure 1A,1B). An 11-Fr guiding sheath facilitated the insertion of a 10-Fr ICE catheter (SoundStar; Biosense Webster, Irvine, CA, USA) into the right atrium, where rotating the catheter reveals the tricuspid annulus, forming the “Home View”. Subsequently, the first handle was rotated 30° counterclockwise to form a “P bend”, allowing the catheter to be advanced across the tricuspid valve into the right ventricle, resulting in the disappearance of the tricuspid valve. The interventricular septum and mitral valve are then visible. At this stage, the second handle was rotated counterclockwise by 30–60° to create an “L bend”, until the long-axis view of the left ventricle was displayed. Finally, an A bend of approximately 30° was made to clearly visualize the chordae tendineae attached to the A2 scallop of anterior mitral leaflet. Following the exchange of the 7-Fr arterial sheath with a guidewire, an 11.5-Fr CARTO VIZIGO Bi-Directional Guiding Sheath (Biosense Webster) was introduced into the left ventricular outflow tract. This steerable sheath was then redirected towards the A2 scallop of the mitral valve. Subsequently, biopsy forceps (Jawz^TM; Argon Medical Devices, Plano, TX, USA) were guided through the steerable sheath under real-time ICE (Vivid^TM IQ, GE Healthcare, Waukesha, WI, USA) rendering to seize and extract the marginal chordae of the A2 scallop (Figure 1C-1E). The degree of MR was determined by ICE, and these procedures were reiterated until MR was moderate (Figure 1F). The carotid artery and jugular vein were sutured using silk sutures, and the skin incision was subsequently closed.
• TTE Group: a 7-Fr short guiding sheath was inserted through a carotid artery puncture. The 7-Fr guiding sheath was exchanged with a guidewire, followed by the insertion of an 11.5-Fr steerable sheath into the left ventricular outflow tract. The steerable sheath was deflected and directed towards the A2 scallop of the mitral valve (Figure 2A,2B). The procedure was performed under TTE guidance using a 3.3 MHz transducer (S9-2, Philips Healthcare, Royal Philips Electronics) to enhance image resolution, with the right parasternal long-axis four-chamber view employed (Figure 2C). Subsequently, biopsy forceps were inserted through the steerable sheath to seize and extract the marginal chordae of the A2 scallop (Figure 2B,2D). The degree of MR was determined by TTE, and the aforementioned steps were repeated until moderate regurgitation became apparent (Figure 2D). The carotid artery was sutured using silk sutures, and the skin incision was subsequently closed.

Figure 1 Establishment of an MR animal model by chordae tendineae transection under ICE guidance. (A) Picture of surgical procedure. (B) Schematic illustration of the Small-tailed Han sheep. (C) Schematic illustration of chordae tendineae destruction via ICE-guided biopsy forceps. (D) Representative fluoroscopic image of ICE catheter, steerable sheath, and biopsy forceps. (E) Intraoperative ICE image. (F) Representative echocardiography showing the intraoperatively induced regurgitant jet area. CT, chordae tendineae; ICE, intracardiac echocardiography; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; MV, mitral valve; PM, papillary muscle.

Figure 2 Establishment of an MR animal model via chordae tendineae transection under TTE guidance. (A) Schematic illustration of chordae tendineae destruction via TTE-guided biopsy forceps. (B) Representative fluoroscopic image of steerable sheath and biopsy forceps. (C) Intraoperative TTE image. (D) Representative echocardiography showing the intraoperatively induced regurgitant jet area. CT, chordae tendineae; LA, left atrium; LV, left ventricle; MR, mitral regurgitation; MV, mitral valve; PM, papillary muscle; TTE, transthoracic echocardiography.

Postoperatively, extubation was conducted upon the animal’s recovery from anesthesia, and it was then transferred to a recovery room for further observation and care. Ceftiofur sodium (5 mg/kg, im, bid) was administered for 3 days and furosemide (10 mg, im, qd) for 7 days. Echocardiography and electrocardiography were repeated to document the postoperative cardiac function and mitral valve regurgitation of the experimental animal.

Echocardiography

After the operation, the sheep was examined by transthoracic ultrasound at 7 days, 2 months, and 3 months for review until the end of the experiment. The animals were anesthetized with propofol (1.5–3 mg/kg) and positioned in the right lateral position. Two-dimensional, M-mode, and Doppler echocardiography (EPIQ 7C; Philips Healthcare Royal Philips Electronics) equipped with a 2.5 MHz transducer were conducted to evaluate the cardiac structure and function, including the regurgitation area, left atrial dimension (LAD) including left atrial anteroposterior, superoinferior, and mediolateral diameters, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricle internal diameter in diastole (LVIDd), left ventricle internal diameter in systole (LVIDs), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). These measurements were performed in accordance with the current recommendations of the American Society of Echocardiography. We assessed the severity of regurgitation using the regurgitant jet area: less than 4 cm² indicated mild regurgitation, 4–8 cm² indicated moderate regurgitation, and greater than or equal to 8 cm² indicated severe regurgitation. The left atrial anteroposterior diameter was measured at end-systole in the left ventricular long-axis view, whereas the left atrial superoinferior and mediolateral diameters were measured in the apical four-chamber view. The LVEDV and LVESV were calculated using the Simpson’s biplane method from the apical 4-chamber and 2-chamber views, and the LVEF was calculated according to the formula: LVEF = (LVEDV − LVESV)/LVEDV × 100%. The LVIDd and LVIDs were measured in the apical 4-chamber view during end-diastole and end-systole, respectively. LVFS was derived using the formula: LVFS = (LVIDd − LVIDs)/LVIDd × 100%.

Cardiac anatomy

At the conclusion of the follow-up period, the experimental animals were humanely euthanized to conduct a detailed examination of the cardiac anatomy. The macroscopic appearance of the heart was observed, the left atrium was opened and cut, and the left ventricle wall was dissected from the anterolateral commissure thorough anterior papillary muscle. The mitral valve and chordae tendineae were fully exposed, and the damage to the chordae tendineae of the mitral valve was observed.

Statistical analysis

All data were analyzed using the software SPSS 29.0 (IBM Corp., Armonk, NY, USA) and presented as mean ± standard deviation. Two-way analysis of variance (ANOVA) with repeated measures was utilized to assess variances of regurgitation area between groups and measurement times. Fisher’s exact test was applied to analyze the distribution of MR severity (mild vs. moderate-severe) between the 2 groups on the 7th, 60th, and 90th day post-operation. Intergroup comparisons were conducted using independent-samples t-tests, whereas intragroup comparisons were performed using paired-samples t-tests. It was considered statistically significant when P value was less than 0.05.

Results

Surgical results

Postoperatively, both groups successfully established MR models in all 12 sheep; in the ICE group, 1 sheep succumbed to acute left heart failure on the 65th day post-operation due to excessive regurgitation, whereas the remaining 11 sheep did not experience any postoperative complications, including heart failure, pulmonary edema, wound infection, pulmonary infection, or other adverse events, and survived until the end of the observation period.

Echocardiography

Preoperative ultrasound examinations revealed the absence of MR in both the TTE and ICE groups. Postoperatively, all sheep exhibited varying degrees of MR at different time points (Table 1). There was no intergroup difference in regurgitation area immediately postoperatively (P=0.287). However, at 7 days, 2 months, and 3 months postoperatively, the regurgitation area in the ICE group was larger than that in the TTE group (P=0.012, P=0.031, P=0.005, respectively), and the TTE group was confirmed to have transitioned to a mild regurgitation at 3 months postoperatively (Table 1). A 2-way ANOVA with repeated measures revealed an intergroup difference (P=0.017), intragroup difference (P<0.001), and a significant interaction effect between group and time (P=0.013). The line graph in Figure 3 shows that regurgitation in the ICE group tended to stabilize postoperatively, whereas in the TTE group, regurgitation decreased at 7 days postoperatively. On postoperative day 7 and at 2 months, 1 out of 6 sheep in the TTE group showed moderate-severe regurgitation (≥4 cm²), whereas all 6 sheep in the ICE group exhibited moderate-severe regurgitation (Figure 4A,4B). By the third month, none of the 6 sheep in the TTE group demonstrated moderate-severe regurgitation, whereas 5 sheep in the ICE group still showed moderate-severe regurgitation (excluding 1 sheep that died of heart failure due to severe regurgitation on postoperative day 65) (Figure 4C). Fisher’s exact test indicated statistically significant differences in distribution of MR severity between the 2 groups at 7 days, 2 months, and 3 months postoperatively (P=0.015, P=0.015, P=0.002, respectively) (Figure 4A-4C).

Figure 3 Two-way ANOVA with repeated measures was utilized to assess variances of regurgitation area between groups and measurement times. P1: P value of intergroup comparison. P2: P value of intragroup comparison. P3: P value of interaction effect. Simple effects analysis for group differences at specific time points, *, P<0.05; **, P<0.01. Error bars: SEM. ANOVA, analysis of variance; AS, after surgery; BS, before surgery; D7, 7 days postoperatively; D60, 60 days postoperatively; D90, 90 days postoperatively; ICE, intracardiac echocardiography; SEM, standard error of the mean; TTE, transthoracic echocardiography.

Figure 4 Fisher’s exact test for comparing the distribution of regurgitation severity (mild vs. moderate-severe) between groups on the 7th, 60th, and 90th day post-operation. The red bars represent the number of sheep that showed moderate-severe regurgitation, whereas the blue bars represent the number of sheep that exhibited mild regurgitation. (A) D7. (B) D60. (C) D90, 1 sheep in the ICE group was excluded due to death from severe regurgitation on postoperative day 65. D7, 7 days postoperatively; D60, 60 days postoperatively; D90, 90 days postoperatively; ICE, intracardiac echocardiography; TTE, transthoracic echocardiography.

An independent samples t-test found no intergroup difference in LAD before the operation (Table 1). The left atrial superoinferior diameter of the ICE group was higher than that of the TTE group at each time point after the operation (P=0.008, P=0.032, P=0.050, P=0.024, respectively). The left atrial mediolateral diameter in the ICE group was greater than that in the TTE group both immediately postoperatively and 3 months postoperatively (P=0.020, P=0.016, respectively). However, there was no intergroup difference in the anteroposterior diameter of the left atrium at any follow-up time point postoperatively. The left atrial mediolateral diameter in the ICE group increased at all postoperative time points compared to the preoperative measurements; the anteroposterior diameter increased immediately postoperatively, 7 days postoperatively, and 3 months postoperatively; and the superoinferior diameter increased immediately postoperatively and 7 days postoperatively compared to preoperative values (Table 1). In the TTE group, the anteroposterior diameter increased immediately postoperatively and at 7 days postoperatively, and the the mediolateral diameter increased immediately postoperatively (Table 1). However, there was no intragroup difference in the superoinferior diameter at any postoperative time point (Table 1).

Preoperative echocardiography revealed no abnormalities in left ventricular systolic function between the 2 animal groups, with no intergroup difference in LVEF and LVFS observed (Table 1). There was no intergroup difference in LVEF and LVFS at each time point after the operation. In the TTE group, the LVEF and LVFS values increased immediately after the surgery compared to the preoperative levels. In the ICE group, no intragroup differences in LVEF and LVFS were observed at various postoperative follow-up intervals compared to preoperative levels (Table 1). Notably, at all postoperative time points, no intergroup differences were observed in LVEDV, LVESV, LVIDd, and LVIDs (Table 1).

Cardiac anatomy

The experimental animals were euthanized for anatomical observation. In the TTE group, no evident ruptures of the chordae attached to the A2 scallop of the mitral valve were observed, merely presenting with some deformities and damage to the valve leaflets. Conversely, in the ICE group, cardiac anatomy indicated the anticipated ruptures of the marginal chordae in the A2 scallop of the mitral valve, as illustrated in Figure 5. The thickening, deformation, and calcification of the valve leaflet was evident in the ICE group (Figure 5).

Figure 5 Cardiac anatomy at post-mortem examination demonstrates the chordae rupture of the anterior mitral leaflet in the ICE group. The arrow indicates the site of chordae rupture. ICE, intracardiac echocardiography.

Discussion

This study successfully established a stable, reliable, and low-mortality large animal model of MR using ICE. Additionally, standardized surgical techniques and short-term postoperative anti-infection and medication protocols were developed.

Transcatheter methods are commonly employed for creating MR animal models, characterized by their minimally invasive and convenient nature. Although several studies have successfully established canines MR models under TTE or TEE guidance, confirming the reliability of TTE and TEE for visualizing intracardiac structures in canines (11,12). Nonetheless, for large ruminants, the uniformity of existing models is often suboptimal, primarily due to the challenges associated with using TTE and TEE in ruminants (10,13). In fact, based on our previous experience with TTE in sheep, the unique thoracic structure of sheep, characterized by a barrel-shaped thorax typical of ruminants, restricts many acoustic windows. Additionally, interference from lung gas and ruminal air hampers the acquisition of clear images of the mitral valve through commonly used human views such as the left parasternal and apical views. We discovered that placing sheep in a right lateral position and visualizing from the right parasternal long-axis four-chamber, enabled relatively clear observation of the mitral valve and chordae (18). However, accurately determining the relative position of the biopsy forceps and the chordae proved challenging, necessitating multiple attempts by our experienced ultrasound technicians. Moreover, our ultrasound technicians attempted to obtain clear images of the chordae tendineae using TEE, but due to the soft and spacious esophagus of sheep, the size of transducers designed for humans is insufficient to adequately contact the walls of the sheep’s esophagus, and the relatively distant position of the left atrium from the esophagus in sheep complicates the acquisition of accurate images of the mitral valve and chordae (18,19). Consequently, acquiring clear images of the chordae tendineae in ruminants using external imaging techniques has posed a considerable challenge. To mitigate the impact of anatomical variation in sheep and obtain higher quality images, ICE emerged as the superior option. ICE involves the insertion of an ultrasound catheter via the peripheral vein to access the heart chambers, enabling direct visualization of high-resolution intracardiac structures (20). We inserted the ultrasound catheter through the jugular vein into the right ventricle, adjusted the control handle and rotated the catheter, and obtained the long-axis view, thereby clearly delineating the position of the primary chordae of the anterior mitral leaflet and the biopsy forceps, facilitating accurate grasping of the chordae. The follow-up results confirmed that the regurgitation induced in the ICE group was more pronounced and stable compared to that in the TTE group. The ICE group maintained moderate-to-severe regurgitation postoperatively, whereas the TTE group, despite successfully establishing moderate or greater regurgitation during the procedure, experienced a gradual reduction in regurgitation postoperatively, eventually transitioning to mild regurgitation. This may be due to the TTE group not damaging critical chordae tendineae during the procedure, allowing the mitral valve to undergo adaptive changes to mitigate regurgitation symptoms. The cardiac anatomy at the end of the follow-up also corroborated this, as no significant chordae tendineae ruptures were found in the TTE group.

This study demonstrated favorable postoperative survival outcomes, with the exception of 1 sheep in the ICE group that succumbed to heart failure on postoperative day 65 due to severe regurgitation. All other subjects survived until the predetermined follow-up endpoint. The implementation of short-term postoperative anti-infective and anti-heart failure therapies proved essential, as these measures effectively reduced the incidence of postoperative complications in the animal models. For cases presenting with significant regurgitation, intensification of anti-heart failure treatment protocols and extension of therapeutic intervention duration are recommended. These approaches facilitate gradual hemodynamic adaptation in the subjects, enabling the transition from induced acute MR to a more clinically representative chronic MR state. Both groups underwent a 3-month postoperative follow-up to monitor the expansion of the left ventricle and left atrium, as well as changes in myocardial contractility. The left atrium in the ICE group exhibited more pronounced expansion compared to the TTE group, whereas there was no significant difference in left ventricular expansion between the 2 groups. This is because, in the early stages of MR, the left ventricle pumps excess blood into the low-pressure left atrium during contraction to prevent left ventricular damage, thus the left atrium shows enlargement earlier than the left ventricle does (7). The regurgitation in the ICE group was more severe than in the TTE group, consequently leading to more pronounced enlargement of the left atrium. Systolic function of the left ventricle was preserved in both groups; the TTE group showed an immediate increase in LVEF and LVFS post-operation, likely due to the milder regurgitation and compensatory enhancement of left ventricular contractility in the early stages of MR, resulting in higher LVEF than pre-operatively. Conversely, the ICE group, experiencing more severe regurgitation, pumped more blood into the left atrium during ventricular contraction, despite preserved contractile function, with no increase in LVEF compared to pre-operation.

Preclinical applications

Our ICE-guided MR model can be utilized for pathophysiological research related to MR. Postoperatively, with short-term anti-heart failure therapy, the animal models exhibited significant yet stable regurgitation. We observed left atrial enlargement, whereas left ventricular volume and ventricular systolic function remained unchanged, which closely resembles the clinical progression of chronic MR. Additionally, our model can serve as a high-precision platform for TMVI training and education. The simplicity of the modeling procedure and the significant regurgitation achieved are the key advantages of our model. By establishing a standardized modeling protocol, we can provide MR models for numerous medical device companies to evaluate preclinical efficacy and safety.

Limitations

Due to several constraints, including limited resources, this study could not undertake large-scale research, thus further comprehensive investigations in both basic and clinical applications remain to be conducted. The current models primarily focus on acute MR, with relatively short follow-up durations. This limitation prevents the comprehensive investigation of the long-term pathophysiological changes associated with chronic MR, which is more commonly encountered in clinical practice.

Conclusions

ICE serves as an enhanced imaging modality for the establishment of a stable, reliable and reproducible MR large animal model via transcatheter methods. This model is applicable for preclinical evaluation of interventional devices and research on pathophysiology, thereby advancing the diagnosis and treatment of mitral insufficiency.

Acknowledgments

The authors extend heartfelt thanks to all who have provided invaluable assistance and support throughout the course of this study.

Footnote

Reporting Checklist: The authors have completed the ARRIVE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1782/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1782/dss

Funding: This study was supported by General Project of Jiangsu Health Commission (No. M2021009), the Key Program of Taizhou School of Clinical Medicine, Nanjing Medical University (No. TZKY20220305), the Key Research and Development Project of Xuzhou City (No. KC21163), the Management Innovation Research Fund of Jiangsu Provincial Hospital Association (No. JSYGY-1-2020-753), China Postdoctoral Science Foundation (No. 2022M721401), and the National Natural Science Foundation of China (grant No. 82270330) to M.C.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1782/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. All animal experiments were performed under a project license (No. MFL-IACUC-2023-040V1.0) granted by the Institutional Animal Care and Use Committee of CMC Large Animal Research Center, in compliance with Chinese National Regulations on the Administration of Laboratory Animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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