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.
Highlights
Novel coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]
We found that Angiotensin-converting enzyme 2 (ACE2) was expressed in CMs, vascular endothelial cells, fibroblasts, smooth muscle cells and immune cells in normal hearts, and its expression was further increased in several cell subsets in the failing hearts
Since there is a positive correlation between the expressions of brain natriuretic peptide (BNP) and ACE2, we further analyzed the clinical outcome, inflammation markers, and blood BNP levels in COVID-19 patients retrospectively. These findings provide important insights to advance our understanding of the interplay between ACE2, viral infection and inflammation, as well as cardiac injury and failure
Summary
Novel coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. COVID19 patients with pre-existing conditions, such as hypertension and coronary heart disease, have worse clinical outcomes than those without these comorbidities [5,6,7]. In this regard, these findings may point towards the presence of a vicious cycle between SARS-CoV-2 infection and cardiac dysfunction or HF [6]. A recent study from Zou et al reported that ∼7% cardiomyocytes (CMs) express ACE2 in normal human cardiac tissues [12], suggesting that some CMs can be directly infected by SARS-CoV-2. ACE2 gene expression in different cardiomyocyte subsets, as well as its dynamic changes in failing human hearts at the single cell level, are totally unknown
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