Table_1_SARS-CoV-2 infection causes prolonged cardiomyocyte swelling and inhibition of HIF1α translocation in an animal model COVID-19.pdf

Recovered COVID-19 patients often display cardiac dysfunction, even after a mild infection. Most current histological results come from patients that are hospitalized and therefore represent more severe outcomes than most COVID-19 patients face. To overcome this limitation, we investigated the cardiac effects of SARS-CoV-2 infection in a hamster model. SARS-CoV-2 infected hamsters developed diastolic dysfunction after recovering from COVID-19. Histologically, increased cardiomyocyte size was present at the peak of viral load and remained at all time points investigated. As this increase is too rapid for hypertrophic remodeling, we found instead that the heart was oedemic. Moreover, cardiomyocyte swelling is associated with the presence of ischemia. Fibrin-rich microthrombi and pericyte loss were observed at the peak of viral load, resulting in increased HIF1α in cardiomyocytes. Surprisingly, SARS-CoV-2 infection inhibited the translocation of HIF1α to the nucleus both in hamster hearts, in cultured cardiomyocytes, as well as in an epithelial cell line. We propose that the observed diastolic dysfunction is the consequence of cardiac oedema, downstream of microvascular cardiac ischemia. Additionally, our data suggest that inhibition of HIF1α translocation could contribute to an exaggerated response upon SARS-CoV-2 infection.

新型冠状病毒肺炎（COVID-19）康复患者常出现心脏功能异常，即便曾为轻症感染者。当前多数组织学研究结果均来自住院患者，因此其反映的病情严重程度高于绝大多数新冠感染者的实际病程。为克服这一研究局限，本研究利用仓鼠模型，探讨了严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染对心脏的影响。研究发现，感染SARS-CoV-2的仓鼠在新冠康复后出现了舒张功能异常。组织学分析显示，心肌细胞体积增大在病毒载量峰值阶段即可检出，并在所有被检测的时间点持续存在。由于该体积增大的速度过快，不符合肥厚性重构的特征，我们进一步发现仓鼠心脏存在水肿。此外，心肌细胞肿胀与缺血现象相关。在病毒载量峰值阶段可观测到纤维蛋白富集型微血栓及周细胞丢失，进而导致心肌细胞内缺氧诱导因子1α（HIF1α）水平升高。令人意外的是，SARS-CoV-2感染可抑制HIF1α向细胞核的转位，这一现象在仓鼠心脏、培养的心肌细胞及上皮细胞系中均有观测到。我们提出，本次观测到的舒张功能异常是心脏微血管缺血下游通路中，心脏水肿所导致的结果。此外，本研究数据表明，HIF1α转位抑制可能会加剧SARS-CoV-2感染后的机体应答反应。