Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; GnomeDX, Powell, OH, USA.
Ann Diagn Pathol. 2022 Oct;60:151983. doi: 10.1016/j.anndiagpath.2022.151983. Epub 2022 May 29.
Cardiac manifestations are common in severe COVID-19. This study compared the histologic, viral, and molecular findings in cardiac tissue in fatal COVID-19 (n = 11) and controls (n = 11). In situ hybridization (SARS-CoV2 RNA) and immunohistochemistry for viral proteins and the host response were quantified for the samples and compared with qRTPCR and Western blot data. Control hearts showed a high resident population of macrophages that had variable ACE2 expression. Cardiac ACE2 expression was 10× greater in the heart tissues of cases and controls with obesity or type II diabetes. Multifocal endothelial cell swelling and degeneration, perivascular edema plus microvascular thrombi were unique to the cases. SARS-CoV2 RNA and nucleocapsid protein were rarely detected in situ in any COVID-19 heart. However, in each case abundant SARS-CoV-2 spike protein was evident. Co-expression experiments showed that the spike protein localized mostly to the ACE2+ interstitial macrophages/pericytes that were activated as evidenced by increased IL6 and TNFα expression. Western blots confirmed the presence of the viral spike protein, but not the nucleocapsid protein, in the cardiac homogenates. The intercalated disc proteins connexin 43, the primary cardiac gap junction protein, and Na1.5, the predominant cardiac sodium channel, each showed marked lateral migration in the myocytes in the cases, which would increase the risk of reentrant arrhythmias. It is concluded that the viral spike protein, endocytosed by macrophages/pericytes, can induce a myocarditis with the possibility of conduction dysfunction due to abnormal localization of key intercalated disc proteins.
心脏表现常见于重症 COVID-19。本研究比较了 11 例致命 COVID-19（病例组）和 11 例对照（对照组）心脏组织中的组织学、病毒和分子发现。对样本进行了原位杂交（SARS-CoV2 RNA）和病毒蛋白及宿主反应的免疫组化检测，并与 qRT-PCR 和 Western blot 数据进行了比较。对照组心脏显示出高驻留的巨噬细胞群体，其 ACE2 表达具有变异性。在肥胖或 2 型糖尿病的病例和对照组中，心脏 ACE2 表达增加了 10 倍。多灶性内皮细胞肿胀和变性、血管周围水肿伴微血栓是病例的独特表现。SARS-CoV2 RNA 和核衣壳蛋白很少在任何 COVID-19 心脏中进行原位检测。然而，在每个病例中，都有大量的 SARS-CoV-2 刺突蛋白明显存在。共表达实验表明，刺突蛋白主要定位于 ACE2+间质巨噬细胞/周细胞，这些细胞被激活，表现为 IL6 和 TNFα 表达增加。Western blot 证实了心脏匀浆中存在病毒刺突蛋白，但不存在核衣壳蛋白。连接蛋白 43，主要的心脏缝隙连接蛋白，和 Na1.5，主要的心脏钠通道，在病例中每个都显示出心肌细胞中明显的侧向迁移，这会增加折返性心律失常的风险。结论是，内吞的巨噬细胞/周细胞中的病毒刺突蛋白可引起心肌炎，并可能因关键闰盘蛋白的异常定位而导致传导功能障碍。
