1Universitätsklinikum Heidelberg Innere Medizin VIII, Institut für Experimentelle Kardiologie Heidelberg, Deutschland
Background: SARS-CoV-2's multiorgan involvement sparks debate on its impact on the hearts of COVID-19 patients. K18 transgenic mice express human ACE2 in epithelial cells (K18-hACE2-Tg) but not in cardiomyocytes. We established a mouse model introducing human ACE2 expression in cardiomyocytes to investigate SARS-CoV-2's potential heart infection, replication, and effects on cardiac function.
Methods: 8-week-old K18-hACE2-Tg mice, male and female, were infected with AAV9-hACE2 (AAV9-hACE2/K18-hACE2-Tg) or AAV9-YFP (AAV9-YFP/K18-hACE2-Tg) as a control. After three weeks, mice were intranasally exposed to SARS-CoV-2. We assessed virus replication, disease progression, cardiac function, immune cell filtration, and gene expression. Mice were sacrificed at 5 days post-infection (dpi). Additionally, cardiomyocytes in culture were transduced with AAV6-Nucleocapsid or AAV6-YFP.
Results: K18-hACE2-Tg mice exposed to SARS-CoV-2 showed increased viral lung but no heart replication. COVID-19 symptoms worsened at 3-4 dpi. AAV9-hACE2/K18-hACE2-Tg mice exhibited exacerbated symptoms, while both control groups maintained cardiac function without dysfunction throughout disease progression. RNA-seq data revealed modest heart SARS-CoV-2 RNA increase but substantial lung increase. Gene set enrichment analysis showed heart upregulation of TNFα, NFκB, and apoptosis, and downregulation of IFNα/γ signaling. Lung analysis indicated similar heart upregulation, along with hypoxia and TGFβ pathways and IFNα/γ downregulation. Interestingly, hearts did not show immune filtration changes, while AAV9-hACE2/K18-hACE2-Tg lungs showed reduced NK and CD8+ cell filtration, potentially explaining increased lung Sars-Cov-2 infection/replication. In cultured cardiomyocytes, AAV6-Nucleocapsid reduced interferon-related gene mRNA levels.
Conclusion: The presence of hACE2 in the heart permits SARS-CoV-2 access to cardiomyocytes without viral replication. Detection of SARS-CoV-2 in the heart correlates with advanced disease progression but no cardiac dysfunction, unveiling heart-lung crosstalk triggered by viral sensing in cardiomyocytes. Further study is required to understand cardiomyocyte mechanism/roles in lung and systemic immune responses to SARS-CoV-2 infection.