ABSTRACT
BACKGROUND: SARS-CoV-2-mediated COVID-19 may cause sudden cardiac death (SCD). Factors contributing to this increased risk of potentially fatal arrhythmias include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs. However, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown. OBJECTIVE: To assess the cellular and electrophysiological effects of direct SARS-CoV-2 infection of the heart using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS: hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator. RESULTS: Transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large "tsunami"-like waves, and increased calcium transient amplitude. After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal. CONCLUSION: The SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte's repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.
Subject(s)
COVID-19 , Induced Pluripotent Stem Cells , Long QT Syndrome , Humans , Myocytes, Cardiac/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Calcium/metabolism , Furin/metabolism , Long QT Syndrome/metabolism , Pandemics , COVID-19/metabolism , SARS-CoV-2/metabolism , Arrhythmias, Cardiac/metabolism , Action Potentials/physiologyABSTRACT
Azithromycin is a macrolide antibiotic. Recent evidence has demonstrated in vitro activity against a wide variety of respiratory tract viruses, including SARS-CoV-2 responsible for the current global pandemic COVID-19. A mechanism of action acting on different phases of the viral cycle is assumed. In addition to its in vitro antiviral properties, some evidence also suggests immunomodulatory and antifibrotic activity. These properties of azithromycin could be useful in the treatment of viral respiratory tract infections such as COVID-19. However, clinical data on the antiviral efficacy of azithromycin in the treatment of respiratory tract infections are inconsistent, both when used as monotherapy and in polypharmacological combination. In addition, cases of azithromycin-induced QT long and malignant arrhythmias are reported. In this short review, we attempt to determine the role of azithromycin in the treatment of viral respiratory tract infections such as COVID-19, therapeutic efficacy, or inefficacy?