Ma Mengqiu, Xu Yanhua, Su Yang, Ong Sang-Bing, Hu Xingdong, Chai Min, Zhao Maojun, Li Hong, Fan Xiaojuan, Chen Yingjie, Xu Dachun, Xu Xiaojiang
Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, Chinese University of Hong Kong (CUHK), Hong Kong, China.
Front Cardiovasc Med. 2021 Feb 23;8:628885. doi: 10.3389/fcvm.2021.628885. eCollection 2021.
COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are associated with poor clinical outcomes. The cellular distribution of Angiotensin-converting enzyme 2 (ACE2), the critical enzyme for SARS-CoV-2 infection, in the human heart is unknown. We explore the underlying mechanism that leads to increased susceptibility to SARS-CoV-2 in patients with cardiovascular diseases and patients of cardiac dysfunction have increased risk of multi-organ injury compared with patients of normal cardiac function. We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts. The results demonstrated that ACE2 is present in cardiomyocytes (CMs) and non-CMs, while the number of ACE2-postive (ACE2+) CMs and ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in the ACE2+ CMs, which is consistent with other studies that ACE2, ANP, and BNP increased in HF patients. We found that genes related to virus entry, virus replication and suppression of interferon-gamma signaling are all up-regulated in failing CMs, and the increase was significantly higher in ACE2+ CMs, suggesting that these CMs may be more vulnerable to virus infection. As the level of expression of both ACE2 and BNP in CMs were up-regulated, we further performed retrospective analysis of the plasma BNP levels and clinical outcomes of 91 COVID-19 patients from a single-center. Patients with higher plasma BNP were associated with significantly higher mortality and expression levels of inflammatory and infective markers. In the failing heart, the upregulation of ACE2 and virus infection associated genes could potentially facilitate SARS-CoV-2 virus entry and replication in these vulnerable cardiomyocyte subsets. COVID-19 patients with higher plasma BNP levels had poorer clinical outcomes. These observations may allude to a potential regulatory association between ACE2 and BNP in mediating myocarditis associated with COVID-19.
患有高血压或心力衰竭（HF）等合并症的COVID-19患者临床预后较差。血管紧张素转换酶2（ACE2）作为SARS-CoV-2感染的关键酶，其在人心脏中的细胞分布尚不清楚。我们探究了心血管疾病患者对SARS-CoV-2易感性增加的潜在机制，并且与心功能正常的患者相比，心脏功能不全患者发生多器官损伤的风险更高。我们分析了正常心脏和衰竭心脏的单细胞RNA测序（scRNA-seq）数据。结果表明，ACE2存在于心肌细胞（CMs）和非心肌细胞中，而在衰竭心脏中，ACE2阳性（ACE2+）心肌细胞的数量以及这些心肌细胞中ACE2基因的表达均显著增加。有趣的是，脑钠肽（BNP）和心房钠尿肽（ANP）在ACE2+心肌细胞中均显著上调，这与其他研究中HF患者体内ACE2、ANP和BNP升高的结果一致。我们发现，与病毒进入、病毒复制以及干扰素-γ信号抑制相关的基因在衰竭心肌细胞中均上调，且在ACE2+心肌细胞中的增加更为显著，这表明这些心肌细胞可能更容易受到病毒感染。由于心肌细胞中ACE2和BNP的表达水平均上调，我们进一步对来自单中心的91例COVID-19患者的血浆BNP水平和临床结局进行了回顾性分析。血浆BNP水平较高的患者死亡率以及炎症和感染标志物的表达水平显著更高。在衰竭心脏中，ACE2和病毒感染相关基因的上调可能会促进SARS-CoV-2病毒在这些易损心肌细胞亚群中的进入和复制。血浆BNP水平较高的COVID-19患者临床结局较差。这些观察结果可能暗示ACE2和BNP在介导与COVID-19相关的心肌炎方面存在潜在的调节关联。
