Digoxin and Standard-of-Care Therapy for Heart Failure Patients with COVID-19: Analysis of Data from the US Military Health System (MHS) Data Repository

Banaag, Amanda; Pollard, Harvey B.; Koehlmoos, Tracey Pérez

doi:10.1007/s40801-023-00360-8

Cited by 3 publications

References 25 publications

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“Cardiac glycosides”—quo vaditis?—past, present, and future?

Fender,

Klöcker,

Boivin-Jahns

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Up to date, digitalis glycosides, also known as “cardiac glycosides”, are inhibitors of the Na+/K+-ATPase. They have a long-standing history as drugs used in patients suffering from heart failure and atrial fibrillation despite their well-known narrow therapeutic range and the intensive discussions on their raison d’être for these indications. This article will review the history and key findings in basic and clinical research as well as potentially overseen pros and cons of these drugs.

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“Cardiac glycosides”—quo vaditis?—past, present, and future?

Fender,

Klöcker,

Boivin-Jahns

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein

Caohuy,

Eidelman,

Chen

et al. 2024

Sci Rep

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SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air–liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling.

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Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 Spike protein

Caohuy

Eidelman

Chen

et al. 2022

Preprint

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Background: SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper- proinflammatory state involves activation of signaling by NFκB and ENaC, and expression of high levels of cytokines and chemokines. Post-infection inflammation may contribute to "Long COVID", and there are also other long term consequences of acute severe COVID-19, which double or triple the chances of dying from any cause within a year. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a lethal proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 Spike protein. Methods: This hypothesis was tested using the hTERT-transformed BCi-NS1.1 basal stem cell, previously derived from small airway epithelia, which were differentiated into a model of small airway epithelia on an air-liquid-interface (ALI). Cyclic AMP-activated CFTR chloride channel activity was measured using an Ussing Chamber. Cell surface-CFTR was labeled with the impermeant biotin method. Results: Exposure of differentiated airway epithelia to SARS-CoV-2 Spike protein resulted in loss of CFTR protein expression. As hypothesized, TNFα/NFκB signaling was activated, based on increased protein expression of TRADD, the first intracellular adaptor for the TNFα/TNFR1 complex, TNFR1, the TNFα receptor, phosphorylated IκBα, and the chemokine IL8. ENaC activity was also activated, based on specific changes in molecular weights for αandγENaC. Exposure of the epithelia to viral Spike protein suppressed cAMP-activated CFTR chloride channel activity. However, addition of 30 nM concentrations of cardiac glycoside drugs ouabain, digitoxin and digoxin, prevented loss of channel activity. ACE2 and CFTR were found to co-immunoprecipitate (co-IP) in both basal cells and epithelia, suggesting that the mechanism for Spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, Spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane, suggesting that failure of CFTR recovery from endosomal recycling might be a mechanism for Spike-dependent loss of CFTR. Conclusion: Based on experiments with this model of small airway epithelia, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by SARS-CoV-2 Spike protein, thus inducing a CFTR-null, cystic fibrosis-like clinical phenotype. Descriptions of COVID-19 in CF carriers with only one copy of wildtype CFTR suggest that this model-based conclusion might be consistent with patient-based experience.

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Digoxin and Standard-of-Care Therapy for Heart Failure Patients with COVID-19: Analysis of Data from the US Military Health System (MHS) Data Repository

Cited by 3 publications

References 25 publications

“Cardiac glycosides”—quo vaditis?—past, present, and future?

“Cardiac glycosides”—quo vaditis?—past, present, and future?

Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein

Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 Spike protein

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