Discovery of drugs to treat cytokine storm-induced cardiac dysfunction using human cardiac organoids

Abstract

SUMMARY SARS-CoV2 infection leads to cardiac injury and dysfunction in 20-30% of hospitalized patients 1 and higher rates of mortality in patients with pre-existing cardiovascular disease 2,3 . Inflammatory factors released as part of the ‘cytokine storm’ are thought to play a critical role in cardiac dysfunction in severe COVID-19 patients 4 . Here we use human cardiac organoids combined with high sensitivity phosphoproteomics and single nuclei RNA sequencing to identify inflammatory targets inducing cardiac dysfunction. This state-of-the-art pipeline allowed rapid deconvolution of mechanisms and identification of putative therapeutics. We identify a novel interferon-γ driven BRD4 (bromodomain protein 4)-fibrosis/iNOS axis as a key intracellular mediator of inflammation-induced cardiac dysfunction. This axis is therapeutically targetable using BRD4 inhibitors, which promoted full recovery of function in human cardiac organoids and prevented severe inflammation and death in a cytokine-storm mouse model. The BRD inhibitor INCB054329 was the most efficacious, and is a prime candidate for drug repurposing to attenuate cardiac dysfunction and improve COVID-19 mortality in humans.