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 ‘cytokine-storm’ induced dysfunction. To identify mechanisms and discover cardio-protective therapeutics, we use a state-of-the-art pipeline combining human cardiac organoids with high throughput phosphoproteomics and single nuclei RNA sequencing. We identify that ‘cytokine-storm’ induced diastolic dysfunction can be caused by a cocktail of interferon gamma, interleukin 1β and poly(I:C) and also human serum from COVID-19 patients. Bromodomain protein 4 (BRD4) is activated along with pathology driving fibrotic and induced nitric oxide synthase genes. BRD inhibitors fully recover function in hCO and completely prevent death in a cytokine-storm mouse model. BRD inhibition decreases transcription of multiple genes, including fibrotic, induced nitric oxide synthase and ACE2, and reduces cardiac infection from SARS-CoV2. Thus, BRD inhibitors are promising candidates to prevent COVID-19 mediated cardiac damage.
Competing Interest Statement
R.J.M., J.E.H., G.A.Q.-R., D.M.T. and E.R.P. are listed as co-inventors on pending patents held by The University of Queensland and QIMR Berghofer Medical Research Institute that relate to cardiac organoid maturation and putative cardiac regeneration therapeutics. J.E.H. is a co-inventor on licensed patents held by the University of Goettingen. R.J.M, E.R.P., D.M.T., B.G. and J.E.H. are co-founders, scientific advisors and stockholders in Dynomics Inc. D.M.T. and B.G. are employees of Dynomics Inc. /Dynomics Pty Ltd. QIMR Berghofer Medical Research Institute has filed a patent on the use of BRD inhibitors.
Footnotes
We now have additional experimental data including work using human COVID-19 serum and also extensive SARS-CoV2 infection studies. The manuscript has been substantially changed throughout.