Cell type-specific expression of the putative SARS-CoV-2 receptor ACE2 in human hearts

Abstract

The coronavirus disease 2019 caused by SARS-CoV-2 infections imposes a major threat for the world's healthcare systems and is leading to thousands of deaths. Angiotensin-converting enzyme 2 (ACE2) has been identified as a potential receptor for SARS coronavirus 1 and is also considered the main receptor for SARS-CoV-2. 2 SARS-CoV-2 binds to ACE2 via its glycosylated outer membrane spike proteins. ACE2 is highly expressed in the lung and heart, and is known for its vital role in the cardiovascular system. 3-5 Although SARS-CoV-2 mainly invades alveolar epithelial cells, it can also cause myocardial injury, as assessed by increased troponin T and NT-proBNP levels accompanying increased cardiovascular symptoms in COVID-19-infected patients. 6,7 It is unclear whether elevated biomarkers of cardiac injury (or long-term effects on the cardiovascular system) are directly caused by viral infection of cardiac tissue or are secondary to hypoxia and systemic inflammation. However, patients with underlying cardiovascular disease represent a significant proportion of the patients who may suffer from a severe course after COVID-19 infection. 8 This situation may be aggravated by findings showing that ACE inhibitors, which are often used to treat cardiovascular diseases, augment the expression of the SARS-CoV-2 receptor ACE2 in lung cells. 9 This is probably mediated by an effect on angiotensin II, which is known to reduce ACE2 expression. 9 Thus, ACE inhibition decreases angiotensin II, leading to an indirect up-regulation of ACE2. 9 The effect of angiotensin II receptor blockers (ARBs), which primarily target the angiotensin receptor 1, is unclear. One may speculate that ARBs indirectly reduce ACE2 levels by augmenting free angiotensin II levels, which in turn is expected to downregulate ACE2 via activating the angiotensin receptor 2. However, the effect of the two different treatments on the expression of ACE2 in the heart requires further investigation.Therefore, we used single nuclei RNA sequencing to determine the expression of ACE and ACE2 in the different cell types of the human heart. Gene expression signatures were detected in cardiac tissues of five patients with aortic stenosis (AS) and two patients with heart failure with reduced ejection fraction (HFrEF) ( Figure 1A) and compared with with samples of one healthy donor heart (age: 63 years, male) that was not used for transplantation. After single nuclei RNA sequencing, data were pooled, and unsupervised clustering was performed with a total of 57 601 nuclei. We found 18 distinct clusters. Using cell type-specific gene markers, major cell types were annotated, including cardiomyocytes (six clusters), fibroblasts (one cluster), endothelial cells (three clusters), leucocytes (two clusters), pericytes (one cluster), and smooth muscle cells (one cluster) ( Figure 1B-D). ACE2 was expressed in cardiomyocytes (Cluster 0 and 1) and mural cells, particularly pericytes (Cluster 4), and was detected at a lower expression level in fibroblasts, endothelial cell, and leucocytes...

Detection of viral SARS‐CoV‐2 genomes and histopathological changes in endomyocardial biopsies

“…22 Recent reports showed that besides pericyctes ACE-2 is expressed to different levels also in cardiomyocytes, endothelial cells, fibroblasts, and leucocytes. 23 However, ACE-2 expression does not argue for permissive infection of a respective target cell by SARS-CoV-2. On the other hand, recent reports have demonstrated that SARS-CoV-2 genomes could be detected besides airway epithelium cells also in the intestinal enterocytes, spleen, liver, kidney, and heart.…”

SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

“…Living human heart slices (300 µm) were generated and cultured as described 9 Viral infection SARS-CoV-2-FFM1 and FFM2 were isolated and propagated in Caco-2 cells as described 13,14 . The viral stock was diluted to desired MOI in medium containing 1% fetal bovine serum and incubated with cells for 2 h. Then the infectious inoculum was removed and cells were supplemented with the respective culture medium 11 .…”

Lack of Benefit in COVID-19 Patients Treated with Hydroxychloroquine or Chloroquine: A Systematic Review and Meta-Analysis

“…Despite the fact that HCQ/CQ were commonly used for rheumatoid arthritis and systemic lupus erythematosus in the general population, there has been major concern with widespread use of these medications for COVID-19 due to possible QTc prolongation and induction of life-threatening arrhythmias. There is general consensus that QTc prolongation after HCQ/CQ use may occur in a dose-dependent way [11,[32][33][34][35]. Previous studies demonstrated that HCQ/CQ block the hERG potassium channels, extending ventricular repolarization and action potentials, and hence, may trigger ventricular tachyarrhythmias [36,37].…”