Abstract

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through 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 1ß, 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 (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs 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 Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Authors	Mills, Richard J; Humphrey, Sean J; Fortuna, Patrick R J; Lor, Mary; Foster, Simon R; Quaife-Ryan, Gregory A; Johnston, Rebecca L; Dumenil, Troy; Bishop, Cameron; Rudraraju, 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 P A; Bald, Tobias; James, David E; Hudson, James E
Journal	CELL
Pages	2167-2182.e22
Volume	184
Date	1/01/2021
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.cell.2021.03.026