Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition.

As an enveloped virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivers its viral genome into host cells via fusion of the viral and cell membranes. Here, we show that ANO6/TMEM16F-mediated cell surface exposure of phosphatidylserine is critical for SARS-CoV-2 entry and that ANO6-selective inhibitors are effective against SARS-CoV-2 infections. Application of the SARS-CoV-2 Spike pseudotyped virus (SARS2-PsV) evokes a cytosolic Ca2+ elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries identifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 displays the highest potency and ANO6 selectivity and it inhibits the single-round infection of SARS2-PsV in ACE2/TMPRSS2-positive HEK 293T cells. More importantly, A6-001 strongly inhibits authentic SARS-CoV-2-induced phosphatidylserine scrambling and SARS-CoV-2 viral replications in Vero, Calu-3, and primarily cultured human nasal epithelial cells. These results provide mechanistic insights into the viral entry process and offer a potential target for pharmacological intervention to protect against coronavirus disease 2019 (COVID-19).

Nonspecific intraventricular conduction delay is associated with future occurrence of atrial fibrillation in patients with structurally normal heart.

BACKGROUND: We aimed to elucidate the long-term prognosis of nonspecific intraventricular conduction delay (NIVCD) in patients with structurally normal heart. METHODS: We included 107,838 patients (age, 52.1 ±â€¯15.5 years; men, 46.8%) who underwent electrocardiography in outpatient clinics or medical checkup (unmatched cohort). NIVCD was defined as QRS duration ≥110 ms without meeting the criteria for bundle branch block. Patients with structurally normal heart and sinus rhythm were assigned to the NIVCD and normal QRS groups according to propensity score with matching variables of age, sex, hypertension, and diabetes (matched cohort 1), and additional PR interval (matched cohort 2). Baseline characteristics, electrocardiographic parameters, and clinical outcomes were compared in the unmatched cohort and the matched cohort. RESULTS: In the unmatched cohort, the frequencies of male sex and preexisting atrial fibrillation were significantly higher in the NIVCD group than in the normal QRS group. In matched cohort 1 (n = 690), the NIVCD group exhibited significant slower sinus rate and longer PR interval than the normal QRS group. In matched cohort 2 (n = 598), the cumulative incidence of atrial fibrillation was significantly higher in the NIVCD group than in the normal QRS group during a follow-up period of 8.8 ±â€¯2.9 years. NIVCD significantly increased the risk for AF (hazard ratio, 2.571; 95% confidence interval, 1.074-6.156; p = 0.034). CONCLUSIONS: It is suggested that NIVCD may be associated with future occurrence of atrial fibrillation in patients with structurally normal heart and sinus rhythm.