SARS‐CoV‐2 spike protein acts as a β‐adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID

Background Currently, pathophysiological mechanisms of post‐acute sequelae of coronavirus disease‐19‐cardiovascular syndrome (PASC‐CVS) remain unknown. Methods and results Patients with PASC‐CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome‐coronavirus‐2 spike protein S1 than the non‐PASC‐CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac β‐adrenergic receptor (β‐AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to β 1 ‐ and β 2 ‐AR, but not to D1‐dopamine receptor. These interactions were blocked by β 1 ‐ and β 2 ‐AR blockers. Molecular docking and MST assay of β‐AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both β‐ARs. In cardiomyocytes, spike protein dose‐dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on β‐ARs. Conclusion Severe acute respiratory syndrome‐coronavirus‐2 spike proteins act as an allosteric β‐AR agonist, leading to cardiac β‐AR hyperactivity, thus contributing to PASC‐CVS.