Single-Cell Transcriptome Analysis Decipher New Potential Regulation Mechanism of ACE2 and NPs Signaling Among Heart Failure Patients Infected With SARS-CoV-2
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Abstract
Aims: 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.
Methods and Results: 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.
Conclusion: 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.
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SciScore for 10.1101/2020.04.30.20081257: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study protocol was approved by the ethics committee of Shanghai Tenth People’s Hospital, Tongji University School of Medicine (Shanghai, China).
Consent: Patient informed consent was waived by each ethics committee due to the COVID-19 pandemic.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: First, the experimental approach used in the current study could not determine how …
SciScore for 10.1101/2020.04.30.20081257: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study protocol was approved by the ethics committee of Shanghai Tenth People’s Hospital, Tongji University School of Medicine (Shanghai, China).
Consent: Patient informed consent was waived by each ethics committee due to the COVID-19 pandemic.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitations: First, the experimental approach used in the current study could not determine how ACE2 and NPs are synergistically regulated during HF. However, the finding could certainly encourage further investigation of the crosstalk among ACE2, ANP and BNP, as well as identifying the common transcriptional factors for these genes. Second, the novel findings presented in this study are limited at the transcriptional level. While the posttranscriptional regulation exerts critical roles in regulating the biological function for many proteins, the scRNA-seq data have clearly provided new insights to advance our understanding of the molecular mechanisms for various clinical diseases. Finally, while the present study certainly advances our understanding of ACE2 in the failing heart, the precise role of cardiac ACE2 in regulating HF patients could not be defined. Further experimental and clinical studies regarding ACE2 are warranted.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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