SUMMARY
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.
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. C.H., D.G., L.F., J.J., M.S., N.C.W.W. and E.K. are employed by Resverlogix. S.J.N. has received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute has filed a patent on the use of BETi.
Footnotes
We now have additional experimental data including: 1) Extensive bioinformatics 2) A SARS-CoV2 infection K18-hACE2 mouse model including RNA-seq of lungs and hearts, 3) Assessment of cardiac function in LPS a mouse model, 4) More human patients and correlation with factors in serum, 5) Up-regulation of a key COVID-19 progressing marker, LGALS3BP, in all our inflammation models, 6) Repression of LGALS3BP in all our models by BETi, 7) Assessment of all commercially available BETi that have been in the clinic, 8) Demonstrated efficacy of BD2 targeting drugs, including apabetalone, 9) Regulation of LGALS3BP in phase IIb cardiovascular (non-COVID-19) clinical trials with apabetalone.
