ABSTRACT
Objectives Atrial fibrillation (AF) is the most common arrhythmia in coronary virus disease 2019 (COVID-19) patients, especially in severe patients. A history of AF can exacerbate COVID-19 symptoms. COVID-19 Patients with new-onset AF have prolonged hospital stays and increased death risk. However, the mechanisms and targets of the interaction between COVID-19 and AF have not been elucidated. Materials and methods We used a series of bioinformatics analyses to understand biological pathways, protein-protein interaction (PPI) networks, gene regulatory networks (GRNs), and protein-chemical interactions between COVID-19 and AF and constructed an AF-related gene signature to assess COVID-19 severity and prognosis. Results We found folate and one-carbon metabolism, calcium regulation, and TFG-β signaling pathway as potential mechanisms linking COVID-19 and AF, which may be involved in alterations in neutrophil metabolism, inflammation, and endothelial cell function. We identified hug genes and found that NF-κb, hsa-miR-1-3p, hsa-miR-124-3p, valproic acid, and quercetin may be key regulatory molecules. We constructed a 3-gene signature consisting of ARG1, GIMAP7, and RFX2 models for the assessment of COVID-19 severity and prognosis, and found that they are associated with neutrophils, T cells, and hematopoietic stem cells, respectively. Conclusion Our study reveals a dysregulation of metabolism, inflammation, and immunity between COVID-19 and AF, and identified several therapeutic targets and progression markers. We hope that the results will reveal important insights into the complex interactions between COVID-19 and AF that will drive novel drug development and help in severity assessment.
ABSTRACT
Hydroxychloroquine (HCQ), clinically established in antimalarial and autoimmune therapy, recently raised cardiac arrhythmogenic concerns when used alone or with azithromycin (HCQ+AZM) in Covid-19. We report complementary, experimental, studies of its electrophysiological effects. In patch clamped HEK293 cells expressing human cardiac ion channels, HCQ inhibited IKr and IK1 at a therapeutic concentrations (IC50s: 10 ± 0.6 and 34 ± 5.0 µM). INa and ICaL showed higher IC50s; Ito and IKs were unaffected. AZM slightly inhibited INa, ICaL, IKs, and IKr, sparing IK1 and Ito. (HCQ+AZM) inhibited IKr and IK1 (IC50s: 7.7 ± 0.8 and 30.4 ± 3.0 µM), sparing INa, ICaL, and Ito. Molecular induced-fit docking modeling confirmed potential HCQ-hERG but weak AZM-hERG binding. Effects of µM-HCQ were studied in isolated perfused guinea-pig hearts by multielectrode, optical RH237 voltage, and Rhod-2 mapping. These revealed reversibly reduced left atrial and ventricular action potential (AP) conduction velocities increasing their heterogeneities, increased AP durations (APDs), and increased durations and dispersions of intracellular [Ca2+] transients, respectively. Hearts also became bradycardic with increased electrocardiographic PR and QRS durations. The (HCQ+AZM) combination accentuated these effects. Contrastingly, (HCQ+AZM) and not HCQ alone disrupted AP propagation, inducing alternans and torsadogenic-like episodes on voltage mapping during forced pacing. O'Hara-Rudy modeling showed that the observed IKr and IK1 effects explained the APD alterations and the consequently prolonged Ca2+ transients. The latter might then downregulate INa, reducing AP conduction velocity through recently reported INa downregulation by cytosolic [Ca2+] in a novel scheme for drug action. The findings may thus prompt future investigations of HCQ's cardiac safety under particular, chronic and acute, clinical situations.