第一部分 封堵器内皮化心脏CTA评估与病理学相关性研究

背景：目前，经导管封堵术已成为多种先天性心脏病（如ASD、VSD、PDA等）的首选治疗策略。随着封堵器在全球范围内的广泛应用，临床上封堵器延迟内皮化的病例报道逐渐增多。然而，封堵器内皮化的体内临床评估仍然面临巨大挑战。现有影像学方法对封堵器内皮化的评估均存在一定的局限性且缺乏系统的病理学对照研究。本研究旨在探究心脏CTA评估封堵器内皮化程度的临床应用价值及其与病理学结果的相关性。

方法：回顾性分析2010年1月至2022年5月在本院接受外科手术取出封堵器的25例患者(年龄：50.00 [17.00, 52.00] 岁；女性12例)。所有患者在术前1个月内采用双源计算机断层扫描 (Dual-source Computed Tomography, DSCT) 进行心脏CTA检查，扫描参数包括管电压120 kV，管电流自动调节，对比剂采用碘普罗胺 (370 mg I/mL) 静脉注射。封堵器种类包括ASD封堵器（16例）、PDA封堵器（5例）、VSD封堵器（2例）、血管塞（1例）和左房耳 (Left Atrial Appendage, LAA) 封堵器（1例）。通过心脏CTA评估封堵器内是否存在对比剂摄取，并与术后病理学检查结果（包括纤维化率、内皮化率、血栓形成、炎性细胞浸润及钙化灶形成等）进行对比分析，验证心脏CTA评估内皮化的可行性和准确性。采用Spearman相关分析评估封堵器表面内皮化率与植入时间、封堵器大小（封堵器腰部直径）及抗血栓治疗时间等因素的相关性。

结果：76.00%的患者心脏CTA显示封堵器内存在对比剂摄取。病理学检查证实所有出现对比剂摄取的封堵器表面均存在纤维组织和新生内皮覆盖不完全，其中47.37%的患者封堵器表面完全无覆盖，其余患者封堵器表面部分组织覆盖。在无对比剂摄取的封堵器表面，均观察到完整的纤维组织覆盖，但仍有66.67%的患者存在新生内皮覆盖不完全。植入时间超过6个月的封堵器中（14例），71.43%的封堵器左侧伞盘和42.86%的封堵器右侧伞盘存在纤维组织和新生内皮覆盖不完全。在这些患者中，28.57%的封堵器左侧伞盘和57.14%的封堵器右侧伞盘显示完整的纤维组织覆盖但内皮覆盖不完全，4例患者病理检查发现封堵器表面有血栓形成。相关性分析显示，植入时间与病理学指标呈显著相关（左侧伞盘纤维化率r = 0.70,P < 0.01; 右侧伞盘纤维化率r = 0.82, P < 0.01；左侧伞盘内皮化率r = 0.60, P < 0.01; 右侧伞盘内皮化率r = 0.61,P < 0.01）。抗血小板治疗时间与封堵器右侧伞盘纤维化率 (r = 0.46, P < 0.05) 和内皮化率 (r = 0.71, P < 0.01)呈正相关，抗凝治疗时间与右侧伞盘内皮化率呈负相关 (r = -0.42, P < 0.05)。体质量指数 (Body Mass Index, BMI) 与封堵器右侧伞盘内皮化率 (r = 0.42, P < 0.05) 呈正相关。病理检查发现，2例患者封堵器表面存在慢性炎症反应，1例患者封堵器表面检出微小钙化灶。

结论：心脏CTA通过评估封堵器内对比剂摄取情况可以有效判断其表面内皮化程度，并与病理学检查结果对应良好。此外，封堵器延迟内皮化在临床中较为常见，特别是封堵器左侧伞盘更易发生延迟内皮化。需要进一步研究探讨封堵器延迟内皮化的机制及影响因素。

第二部分 房间隔缺损封堵器延迟内皮化心脏CTA评估与多因素分析

背景：经导管封堵器植入术已成为治疗继发孔型ASD的首选方法。病理学研究表明, ASD封堵器内皮化是一个复杂的病理生理学过程,包括纤维组织形成和内皮细胞覆盖两个关键阶段。这一过程从封堵器边缘向中心逐步进行,其完成时间在不同个体间存在较大差异。既往动物实验研究显示ASD封堵器可在3-6个月内完成内皮化，这一结论成为制定术后人体抗血栓治疗方案的主要依据。然而，由于缺乏有效的评估方法，人体内ASD封堵器内皮化机制尚未得到充分研究。近年来研究发现,部分ASD患者术后出现延迟内皮化现象，可能导致血栓形成或感染性心内膜炎等潜在并发症,这提示需重新评估传统认知中3-6个月完全内皮化的观点。本课题组前期研究证实，心脏CTA通过检测对比剂在封堵器内有无摄取能够评估封堵器表面内皮化，并与病理学结果对应良好。本研究旨在以前文第一部分封堵器内皮化心脏CTA评估研究成果为基础，通过心脏CTA初步评估ASD封堵器延迟内皮化的发生率,并探讨ASD封堵器延迟内皮化的影响因素。

方法：回顾性纳入2010年1月至2019年1月行ASD封堵术后超过6个月的119例患者:48例男性，71例女性，年龄 (46.70 ± 14.40) 岁。所有患者术前经食管超声心动图 (Transesophageal Echocardiography, TEE) 测量缺损直径，并采用镍钛合金ASD封堵器行介入治疗。心脏CTA检查采用DSCT进行检查，对比剂采用碘普罗胺 (370 mg I/mL) 静脉注射，注射速率4.00 mL/s -5.00 mL/s。其中，7例患者接受了外科手术取出封堵器。根据对比剂摄取情况将封堵器内皮化程度分为完全内皮化（无明显对比剂摄取）、不完全/部分内皮化（对比剂不完全/部分摄取）和无内皮化（对比剂完全摄取）三类。研究收集的临床资料包括年龄、性别、BMI、ASD缺损大小、封堵器型号、随访时间等因素，采用多因素logistic回归分析确定影响ASD封堵器内皮化的危险因素。

结果：在119例患者中，中位植入时间1.50年，43.70%的患者存在延迟内皮化（36例不完全/部分内皮化，16例无内皮化）。在部分内皮化病例中，对比剂摄取主要发生在左侧伞盘(n = 26)，完全内皮化的比例从植入后0.50-1.00年的14.30%上升到1.00年后的73.80%。体内封堵器厚度是预测内皮化不足的独立危险因素 (比值比[Odds Ratio, OR] = 1.75, 95% 置信区间[Confidence Interval, CI]: 1.39-2.21, P < 0.001)。在18例抗血小板治疗6个月后偏头痛复发的患者中，15例显示不完全内皮化（均位于左侧伞盘）。受试者工作特征曲线(Receiver Operating Characteristic Curve, ROC)分析显示，体内封堵器厚度7.10 mm是区分完全内皮化与不完全内皮化的临界值（敏感度：88.50%；特异度：77.60%；曲线下面积[Area Under the Curve, AUC]: 0.90）。7例取出ASD封堵器的患者，心脏CTA评估结果与病理检查结果一致性良好。

结论：心脏CTA可有效评估ASD封堵器植入后的延迟内皮化，展现良好的影像学-病理学相关性。在植入时间大于6个月的患者中，ASD封堵器的延迟内皮化是临床上常见现象，且与体内封堵器厚度显著相关。下一步需要深入研究ASD封堵器延迟内皮化对术后抗血栓治疗策略的影响。

综述 心脏封堵器内皮化研究进展

摘要： 随着心脏封堵器在先天性心脏病治疗中的广泛应用，其植入后相关并发症一直是临床关注的重点。内皮化作为封堵器植入后关键的病理生理学过程，与并发症的发生密切相关，直接影响患者的长期预后。研究表明，内皮化过程受到多种因素的调控，呈现出从急性期到慢性期的复杂动态变化。临床观察发现，植入后内皮化进程存在显著个体差异，封堵器延迟内皮化可能导致血栓形成和感染性心内膜炎等潜在并发症。本文系统综述了封堵器内皮化的研究现状，重点阐述内皮化的生物学机制、影响因素、评估方法及临床意义。未来的研究应深入探讨延迟内皮化的病理生理学机制，开发具有促进内皮化功能的新型封堵器材料，并优化封堵器评估方法和随访策略，以改善病人远期预后。

Part 1：Evaluation of Device Endothelialization with Cardiac Computed Tomography Angiography and Assessment of the Pathological Validation

Background: Transcatheter device closure has been established as the first-line therapeutic strategy for various congenital heart diseases, including atrial septal defect (ASD), patent ductus arteriosus (PDA), and ventricular septal defect (VSD). With the widespread global application of these devices, cases of delayed device endothelialization have been increasingly reported in clinical practice. However, the non-invasive assessment of device endothelialization remains challenging, as current imaging modalities have limitations and lack systematic pathological validation. This study aims to evaluate the utility of cardiac computed tomography angiography (CTA) in assessing device endothelialization and correlate these findings with pathological examination.

Methods: A total of 25 patients (12 females, median age: 50.00 [17.00, 52.00] years) who underwent surgical explantation of cardiac devices between January 2010 and May 2022 were retrospectively analyzed. Preoperative cardiac CTA was performed using a dual-source CT system within one month before device removal. Scanning parameters included 120 kV tube voltage, automatic tube current modulation, and intravenous administration of iopromide    (370 mg I/mL). The explanted devices comprised atrial septal occluders (n = 16), patent ductus arteriosus occluders (n = 5), ventricular septal occluders (n = 2), vascular plug (n = 1), and left atrial appendage occluder (n = 1). CTA evaluation focused on contrast uptake within the devices, and these findings were compared with pathological findings (including endothelial coverage and fibrous tissue formation) to validate the accuracy of CTA in assessing endothelialization. Spearman correlation analysis was conducted to evaluate the correlation between endothelialization rate and the factors such as implantation duration, device size (waist diameter of the device), and antithrombotic therapy duration.

Results: CTA revealed contrast uptake within 76.00% of the explanted devices. Pathological examination confirmed incomplete fibrous tissue and neo-endothelial coverage in all devices showing contrast uptake, with 47.37% demonstrating no coverage and the remainder exhibiting partial coverage. Devices without contrast uptake showed complete fibrous tissue formation, although 66.67% still exhibited incomplete endothelialization. Among 14 devices implanted for more than 6 months, incomplete fibrous tissue and neo-endothelial coverage was observed in 71.43% of left discs and  42.86% of right discs, while 28.57% of left discs and 57.14% of right discs exhibited complete fibrous tissue formation but incomplete endothelialization, with thrombus formation identified in 4 cases. Correlation analysis revealed significant association between implantation duration and pathological parameters, including fibrosis (left disc:  r = 0.70, right disc: r = 0.82) and endothelialization (left disc: r = 0.60, right disc: r = 0.61), all with P < 0.01. The duration of antiplatelet therapy was positively correlated with right disc fibrosis (r = 0.46, P < 0.05) and endothelialization (r = 0.71, P < 0.01), whereas anticoagulation therapy was negatively correlated with right disc endothelialization (r =

-0.42, P < 0.05). Additionally, body mass index (BMI) exhibited positive correlation with right disc endothelialization (r = 0.42, P < 0.05). Additionally, histopathological examination revealed chronic inflammation in 2 cases and microcalcification in 1 case.

Conclusion: Cardiac CTA effectively evaluated device endothelialization by assessing contrast uptake within the devices, and the accuracy of these assessments was validated by pathological examination. The study revealed that delayed endothelialization of device was relatively common in clinical practice, particularly in the left disc of the devices. Further investigation is warranted to elucidate the underlying mechanisms and influencing factors of delayed device endothelialization.

Part 2：Cardiac Computed Tomography Angiography Evaluation and Multivariate Analysis of Delayed Endothelialization in Atrial Septal Defect Device

Background: Transcatheter device closure has become the preferred treatment for secundum atrial septal defects (ASD). Pathological studies have demonstrated that device endothelialization is a complex pathophysiological process involving two key stages: fibrous tissue formation and endothelial cell coverage. This process progresses gradually from the device rim toward the center, with significant individual variations in time to full coverage. Animal studies have suggested that device endothelialization was completed within 3-6 months, which served as the primary basis for antithrombotic therapy protocols in human. However, the absence of comprehensive evaluation methods has hindered a thorough understanding of device endothelialization mechanisms in human. Recent studies have revealed delayed endothelialization in some patients, potentially leading to serious complications such as thrombosis or infective endocarditis, suggesting that the traditional 3-6 month endothelialization process duration needs reassessment. Our previous research has demonstrated that cardiac computed tomography angiography (CTA), by evaluating contrast uptake within devices and correlating with pathological findings from retrieved human device specimens, has established a robust methodology for investigating in vivo device endothelialization. Based on our previous findings on device endothelialization, this study aims to further validate the pathological correlation of cardiac CTA in assessing ASD occluder endothelialization.

Methods: A retrospective study was conducted, including patients (48 males, 71 females; mean age [46.70 ± 14.40] years) who underwent ASD closure with Nickel-titanium alloy septal occluders and cardiac CTA examination was performed at least 6 months after the procedure between January 2010 and January 2019. Defect sizes were measured by transesophageal echocardiography before the procedure, and all patients were treated using Amplatzer septal occluders. Cardiac-CTA was performed using a dual-source CT scanner with intravenous injection of iopromide (370 mg I/mL) at a rate of 4.0–5.0 mL/s. In 7 patients requiring device removal, preoperative CTA findings were correlated with pathological results. Device endothelialization was classified into three categories: complete endothelialization (no contrast uptake), incomplete/partial endothelialization (incomplete/partial contrast uptake), and absence of endothelialization (complete contrast uptake). The study comprehensively collected clinical parameters, including age, gender, body mass index (BMI), defect size, device specifications, and follow-up duration. Multivariate logistic regression analysis was performed to identify independent risk factors for incomplete device endothelialization.

Results: Among 119 patients (median implantation time: 1.50 years), 43.70% demonstrated incomplete endothelialization (36 cases of partial endothelialization and 16 cases without endothelialization). In cases of partial endothelialization, contrast uptake was predominantly observed in the posterior aspect of the left disc (n = 26). The proportion of complete endothelialization increased from 14.30% at 0.50-1.00 years to 73.80% after 1.00 year post-implantation. In vivo device thickness was identified as an independent risk factor for incomplete endothelialization (OR = 1.75, 95% CI: 1.39-2.21, P < 0.001). Among 18 patients who experienced migraine recurrence after 6 months of antiplatelet therapy, 15 showed incomplete endothelialization (all located in the posterior aspect of the left disc). Receiver Operating Characteristic Curve (ROC) analysis revealed that a device thickness of 7.10 mm was the cutoff value for distinguishing complete from incomplete endothelialization (sensitivity: 88.50%, specificity: 77.60%, AUC=0.90).

Conclusion: Cardiac CTA effectively evaluated delayed endothelialization after ASD occluder implantation, showing strong clinicopathological correlation. Delayed endothelialization was common beyond 6 months and significantly associated with device thickness. Further research is needed on antithrombotic strategies following implantation.

Review: Advances in Research on Cardiac Closure Device Endothelialization

Abstract：With the widespread application of cardiac occluders in congenital heart disease, post-implantation complications remained a focal point of clinical concern. Endothelialization, as a critical pathophysiological process following device implantation, was closely associated with the occurrence of complications and directly impacts patients' long-term prognosis. Research has indicated that the endothelialization process was regulated by multiple factors, exhibiting complex dynamic changes from acute to chronic stages. Clinical observations have revealed significant individual variations in the progression of post-implantation endothelialization, with delayed endothelialization potentially resulting in serious complications such as thrombosis and infective endocarditis. This review systematically examines the current research of device endothelialization, focusing on its biological mechanisms, influencing factors, assessment methods, and clinical significance. Future research should explore in greater depth the pathophysiological mechanisms of delayed endothelialization, develop novel device materials with enhanced endothelialization properties, and optimize individualized assessment and follow-up strategies to improve patients' long-term prognosis.