Higher incidence of heart failure and arrhythmias in atrial fibrillation patients hospitalized with covid-19

Introduction: Atrial fibrillation (Afib) is a common arrhythmia with significant morbidity and mortality. The cardiovascular effect of COVID-19 infection in patients with known Afib is poorly understood. The aim of this study was to analyze the cardiovascular outcomes of patients with a history of Afib who were admitted with COVID-19 infection. Methods: A retrospective cohort study of patients hospitalized between January 1 and July 31, 2020 with COVID-19 infection confirmed by polymerase chain reaction (PCR) testing of nasopharynx sample was stratified by history of Afib, and analyzed for patient characteristics and cardiovascular outcomes using Mann-Whitney & χ tests. A p value of <0.05 was used for statistical significance. Results: Among the 321 patients admitted with a positive COVID-19 test, 12% (38) had a history of Afib. This subgroup was significantly older, median age 84.5 vs. 61 and were predominantly male, 66 vs. 34%. They showed a higher prevalence of heart failure with reduced ejection fraction (HFrEF) (26 vs. 6%) and with preserved ejection fraction (HFpEF) (34 vs. 13%), CAD (34 vs. 17%), chronic kidney disease (45 vs. 20%), and dyslipidemia (66 vs. 35%) compared to those admitted without a history of Afib. These patients had a wider QRS interval 101 (88-134) vs. 94 (86-104) and more elevated BNP levels 278 (109-696.5) vs. 234 (35-158). They were also more likely to experience Afib (53 vs. 7%) and ventricular arrhythmias (18 vs. 6%) during hospitalization, but they did not show any statistical difference in terms of mortality rate, ICU admission, use of mechanical ventilation, or 30-day hospital readmission. Conclusion: Patients admitted with COVID-19 with a history of Afib were older and had comorbid cardiovascular disease. Heart failure risk markers such as wider QRS interval and higher BNP levels were more common in the history of Afib subgroup of patients. These patients had a higher incidence of heart failure and arrhythmias but not mortality.

Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1.

A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 and Spike Protein Subunit 1 (preprint)

A hallmark of COVID-19 is a hyperinflammatory state that is associated with severity. Various anti-inflammatory therapeutics have shown mixed efficacy in treating COVID-19, and the mechanisms by which hyperinflammation occurs are not well understood. Previous research indicated that monocytes, a key innate immune cell, undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response in monocytes. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism that was associated with production of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor-. This response was dependent on hypoxia-inducible factor-1, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production in monocytes, and abrogated glycolytic and mitochondrial metabolism. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments in monocytes. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

Atypical monocytes in COVID-19: Lighting the fire of cytokine storm?

Discussion on the observed association between unique populations of circulating monocytes and severity of COVID-19.

Severe COVID-19 and aging: are monocytes the key?

The ongoing pandemic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes a disproportionate number of severe cases and deaths in older adults. Severe SARS-CoV-2-associated disease (coronavirus disease 2019 (COVID-19)) was declared a pandemic by the World Health Organization in March 2020 and is characterized by cytokine storm, acute respiratory distress syndrome, and in some cases by systemic inflammation-related pathology. Currently, our knowledge of the determinants of severe COVID-19 is primarily observational. Here, I review emerging evidence to argue that monocytes, a circulating innate immune cell, are principal players in cytokine storm and associated pathologies in COVID-19. I also describe changes in monocyte function and phenotype that are characteristic of both aging and severe COVID-19, which suggests a potential mechanism underlying increased morbidity and mortality due to SARS-CoV-2 infection in older adults. The innate immune system is therefore a potentially important target for therapeutic treatment of COVID-19, but experimental studies are needed, and SARS-CoV-2 presents unique challenges for pre-clinical and mechanistic studies in vivo. The immediate establishment of colonies of SARS-CoV-2-susceptible animal models for aging studies, as well as strong collaborative efforts in the geroscience community, will be required in order to develop the therapies needed to combat severe COVID-19 in older adult populations.