BET Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection

Mills, Richard J.; Humphrey, Sean J.; Fortuna, Patrick RJ.; Lor, Mary; Foster, Simon R.; Quaife-Ryan, Gregory A.; Johnston, Rebecca L.; Dumenil, Troy; Bishop, Cameron; Ruraraju, Rajeev; Rawle, Daniel J.; Le, Thuy; Zhao, Wei; Lee, Leo; Mackenzie-Kludas, Charley; Mehdiabadi, Neda R.; Halliday, Christopher; Gilham, Dean; Fu, Li; Nicholls, Stephen J.; Johansson, Jan; Sweeney, Michael; Wong, Norman C.W.; Kulikowski, Ewelina; Sokolowski, Kamil A.; Tse, Brian W.C.; Devilée, Lynn; Voges, Holly K.; Reynolds, Liam T.; Krumeich, Sophie; Mathieson, Ellen; Abu-Bonsrah, Dad; Karavendzas, Kathy; Griffen, Brendan; Titmarsh, Drew; Elliott, David A.; McMahon, James; Suhrbier, Andreas; Subbarao, Kanta; Porrello, Enzo R.; Smyth, Mark J.; Engwerda, Christian R.; MacDonald, Kelli PA.; Bald, Tobias; James, David E.; Hudson, James E.

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory ‘cytokine-storm’, a cocktail of interferon gamma, interleukin 1β and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.