Bromodomain Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV2 Infection in Pre-Clinical Models

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.