目的：新型冠状病毒（SARS-CoV-2）感染引起的新型冠状病毒肺炎（COVID-19）不仅导致呼吸系统损伤，还可能引发多系统并发症，尤其是心血管系统的长期损害。然而，SARS-CoV-2在心血管组织中的分布特征及其致病机制尚不完全清楚，本研究旨在探究SARS-CoV-2结构蛋白在心血管组织中的分布特征及揭示病毒蛋白在心血管系统中的潜在作用机制。

方法：本研究纳入26例确诊COVID-19的死亡病例（遗体来源于北京协和医学院遗体捐献站），其中12例为急性感染期死亡病例，14例为康复期死亡病例。所有样本的获取均严格遵循伦理审查要求，并完整记录了捐献者的相关基本信息及临床病史。通过组织病理学检查、免疫组织化学染色和免疫荧光染色的方法，系统分析了SARS-CoV-2结构蛋白在26例COVID-19感染者的尸检（12例急性期，14例康复期）心肺组织中的分布特征及相关心血管病理学改变。

结果：研究结果显示，在12例急性期患者中，SARS-CoV-2的S1、S2、N、E和M蛋白在肺和心脏组织中广泛分布。在肺组织中检测到病毒蛋白表达于肺泡Ⅱ型上皮细胞、血管内皮细胞及间质细胞，其中S1亚基在肺组织血管外膜中呈现特异性分布。在心脏组织中，S1、S2和N蛋白表达于心外膜脂肪细胞、心外膜浸润细胞、血管内皮细胞及心肌细胞。此外，还发现S1亚基在心外膜（11例，91.7%）和血管外膜组织中（11例，91.7%）的特殊分布。在14例康复期患者中，S1和N蛋白仍可检测于肺泡上皮细胞和肺间质细胞、心脏内脂肪细胞、心血管内皮细胞以及心肌细胞。且S1亚基持续分布于心血管外膜（8例，57.1%）和心外膜组织（6例，42.9%）。多重免疫荧光染色证实，S1亚基与血管外膜中的Ⅰ型和Ⅲ型胶原存在共定位关系。在COVID-19急性感染期患者心肌组织中观察到广泛病理变化。病理学分析发现，所有急性期尸检病例均存在心肌间质水肿（12/12，100%），大部分病例存在心肌细胞水肿（11/12，91.7%）、心肌细胞坏死（9/12，75%）、血管内皮损伤（9/12，75%）以及心外膜炎（9/12，75%），部分病例存在病毒性心肌炎（2/12，16.7%）和微血栓（2/12，16.7%）。免疫细胞浸润分析显示，心肌炎浸润的淋巴细胞以CD4+和CD8+ T淋巴细胞为主。尽管进入康复阶段，部分病例仍表现出心肌存在持续的急性损伤残留，其中包括间质水肿（13/14，92.9%）、心肌细胞坏死（7/14，50%）、心肌细胞水肿（9/14，64.3%）、内皮细胞水肿（12/14，85.7%）、心外膜炎（8/14，57.1%）。此外，大部分COVID-19康复期患者心肌组织中还存在慢性进行性改变，包括心肌间质纤维化（12/14，85.7%）、小血管管壁增厚（10/14，71.4%）。其中1例（1/14，7.1%）在感染9个月后心肌内仍存在慢性活动性心肌炎，提示病毒成分的长期滞留可能导致持续性炎症反应和组织损伤。

结论：本研究的创新性发现包括：（1）首次揭示了S1亚基在心外膜和血管外膜组织中的特异性分布；（2）证实了病毒蛋白在康复期患者心肌组织中的长期滞留；（3）阐明了COVID-19相关心脏损伤的潜在病理机制。这些发现为理解SARS-CoV-2的多系统致病机制提供了重要依据，尤其为“长新冠”心血管并发症的防治提供了新的研究方向。未来研究可进一步探索S1亚基在外膜组织中的病理作用及其作为治疗靶点的潜在价值。

Objective: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), not only induces respiratory damage but may also lead to multi-system complications, particularly long-term cardiovascular injuries. However, the spatial distribution of SARS-CoV-2 in cardiovascular tissues and its pathogenic mechanisms remain incompletely understood. This study aimed to investigate the distribution of SARS-CoV-2 structural proteins in cardiovascular tissues and elucidate their potential roles in cardiac injury.

Methods: We enrolled 26 autopsy cases of confirmed COVID-19 fatalities (sourced from the Body Donation Station of Peking Union Medical College), including 12 acute-phase and 14 convalescent-phase deaths. All samples were collected in strict compliance with ethical review requirements, with complete donor demographics and clinical histories documented. Using histopathological examination, immunohistochemistry, and immunofluorescence staining, we systematically analyzed the distribution of SARS-CoV-2 structural proteins (S1, S2, N, E, and M) in cardiopulmonary tissues and associated pathological changes.

Results: In acute-phase patients (n=12), SARS-CoV-2 S1, S2, N, E, and M proteins were widely distributed in pulmonary and cardiac tissues. Viral protein expression was observed in alveolar epithelial cells, vascular endothelial cells, and interstitial cells. Notably, the S1 subunit exhibited specific localization in the vascular adventitia of lung tissues. In cardiac tissues, S1, S2, and N proteins were expressed in epicardial adipocytes, infiltrating immune cells, vascular endothelial cells, and cardiomyocytes. The S1 subunit showed distinctive distribution in the epicardium (11/12, 91.7%) and vascular adventitia (11/12, 91.7%). In convalescent-phase patients (n=14), S1 and N proteins persisted in alveolar epithelium, pulmonary interstitial cells, cardiac adipocytes, vascular endothelium, and cardiomyocytes. Residual S1 was detected in the vascular adventitia (8/14, 57.1%) and epicardium (6/14, 42.9%). Multiplex immunofluorescence confirmed colocalization of S1 with type I and III collagen in the vascular adventitia. Acute-phase myocardial pathology revealed interstitial edema (12/12, 100%), cardiomyocyte edema (11/12, 91.7%), necrosis (9/12, 75%), endothelial injury (9/12, 75%), and epicarditis (9/12, 75%), with occasional myocarditis (2/12, 16.7%) and microthrombi (2/12, 16.7%). Immune infiltrates were predominantly CD4+ and CD8+ T lymphocytes. Convalescent-phase cases exhibited persistent acute injuries, including interstitial edema (13/14, 92.9%), cardiomyocyte necrosis (7/14, 50%), edema (9/14, 64.3%), endothelial swelling (12/14, 85.7%), and epicarditis (8/14, 57.1%). Chronic progressive changes were also observed, such as interstitial fibrosis (12/14, 85.7%) and small-vessel wall thickening (10/14, 71.4%). One case (1/14, 7.1%) demonstrated chronic active myocarditis nine months post-infection, suggesting prolonged viral persistence may drive sustained inflammation and tissue damage.

Conclusion: Key findings include: (1) First identification of S1 subunit enrichment in epicardial and vascular adventitial tissues; (2) Confirmation of long-term viral protein retention in cardiovascular tissues of convalescent patients; (3) Mechanistic insights into COVID-19-associated cardiac injury. These results advance our understanding of SARS-CoV-2’s systemic pathogenesis and inform therapeutic strategies for long COVID-related cardiovascular complications. Future studies should explore the pathological role of adventitial S1 and its potential as a therapeutic target.