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 1B; 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.

中文翻译：

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溴结构域和末端外抑制可阻止炎症诱导的心脏功能障碍和SARS-CoV-2感染（临床前）

COVID-19患者会发生心脏损伤和功能障碍，并增加死亡风险。原因尚不明确，但可能是直接的心脏感染和/或炎症引起的功能障碍。为了确定机制和保护心脏的药物，我们使用了先进的技术流程，将人类心脏类器官与磷酸化蛋白质组学和单核RNA测序相结合。我们确定了炎性细胞因子风暴，干扰素γ，白细胞介素1B的混合物；和聚（I：C）引起的舒张功能障碍。含溴结构域的蛋白质4随病毒反应而被激活，该病毒反应在人心脏类器官和SARS-CoV-2感染的K18-hACE2小鼠心脏中均一致。溴结构域和末端外家族抑制剂（BETi）可恢复hCO的功能障碍，并在小鼠细胞因子风暴模型中完全预防心脏功能障碍和死亡。此外，BETi降低了病毒反应中基因的转录，降低了ACE2表达，并减少了心肌细胞的SARS-CoV-2感染。总之，BETi，包括FDA突破性指定的阿帕贝单独治疗药物，都是有望预防COVID-19介导的心脏损害的候选药物。