Introduction: The heart might participate in systemic immunity through cytokines, hormones, and neurotransmitters. Cardiovascular disease (CVD) patients exhibit severe symptoms upon infections like COVID-19. The SARS-CoV-2 receptor, angiotensin-converting enzyme II (ACE2), is upregulated in cardiomyocytes. To determine whether (1) the heart participates in systemic COVID-19 responses and (2) Sars-CoV-2 promotes cardiac dysfunction, we established a mouse model with human ACE2 expression in cardiomyocytes to examine SARS-CoV-2 infection and disease severity impact.
Methods: Eight-week-old K18-hACE2-Tg mice were infected with AAV9-hACE2 (AAV9-hACE2/K18-hACE2-Tg) or AAV9-YFP (AAV9-YFP/K18-hACE2-Tg) as control, followed by SARS-CoV-2 infection. We assessed viral replication, disease progression, cardiac function, immune infiltration, and transcriptome profiling at five days post-infection. Additionally, human and murine cardiomyocytes were transduced with SARS-CoV-2 particles and stimulated with IFN-α/γ. RNA-seq, secretome analysis, and cardiomyocyte-conditioned media transfer to endothelial and natural killer cells were performed.
Results: AAV9-hACE2/K18-hACE2-Tg mice exhibited exacerbated symptoms versus controls without cardiac dysfunction. RNA-seq revealed modest SARS-CoV-2 RNA increase in heart but substantial lung increase, with upregulated TNFα, NFκB, and apoptosis pathways alongside downregulated IFNα/γ signaling in both organs. In cultured cardiomyocytes, AAV6-Nucleocapsid—but not AAV6-Spike—infection reduced interferon-related gene expression, accompanied by transcriptomic changes in muscle homeostasis, secretome alterations, and regulatory effects on endothelial and NK cells exposed to cardiomyocyte-conditioned media.
Conclusions: hACE2 cardiac presence allows SARS-CoV-2 cardiomyocyte access without viral replication. Cardiac SARS-CoV-2 detection correlates with disease progression, suggesting a heart-lung crosstalk triggered by viral sensing. Cardiomyocytes secrete immune mediators affecting pulmonary epithelial and NK cells, suggesting direct cardiac involvement in systemic immunity.
