Predictors of Premature Ventricular Contractions Development in Patients With SARS-CoV-2 Infection.

Background: Epidemiological studies have demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients often develop atrial fibrillation, premature ventricular contractions (PVCs), and conduction disorders. The manifestation of ventricular cardiac arrhythmias accentuates the risk of sudden cardiac death. Methods: A retrospective study was conducted on the cohort of 1,614 patients admitted for coronavirus disease 2019 (COVID-19). Patients were categorized into two groups based on the occurrence of PVCs. Group I comprised 172 patients diagnosed with PVCs of Lown-Wolf class II - IV upon hospital admission; group II (control group) consisted of 1,442 patients without this arrhythmia. Each patient underwent comprehensive clinical, laboratory, and instrumental evaluations. Results: The emergence of PVCs in individuals afflicted with COVID-19 was associated with a 5.879-fold heightened risk of lethal outcome, a 2.904-fold elevated risk of acute myocardial infarction, and a 2.437-fold increased risk of pulmonary embolism. Upon application of diagnostic criteria to evaluate the "cytokine storm", it was discovered that the occurrence of the "cytokine storm" was notably more frequent in the group with PVCs, manifesting in six patients (3.5%), compared to 16 patients (1.1%) in the control group (P < 0.05). The mean extent of lung tissue damage in group I was significantly greater than that of patients in group II (P < 0.05). Notably, the average oxygen saturation level, as measured by pulse oximetry upon hospital admission was 92.63±3.84% in group I and 94.20±3.50% in group II (P < 0.05). Conclusions: The presence of PVCs in COVID-19 patients was found to elevate the risk of cardiovascular complications. Significant independent predictors for the development of PVCs in patients with SARS-CoV-2 infection include: age over 60 years (risk ratio (RR): 4.6; confidence interval (CI): 3.2 - 6.5), a history of myocardial infarction (RR: 3.5; CI: 2.6 - 4.6), congestive heart failure (CHF) with reduced left ventricular ejection fraction (RR: 5.5; CI: 3.9 - 7.6), respiratory failure (RR: 2.3; CI: 1.7 - 3.1), and the presence of a "cytokine storm" (RR: 4.5; CI: 2.9 - 6.0).

A new thiol-independent mechanism of epithelial host defense against Pseudomonas aeruginosa: iNOS/NO• sabotage of theft-ferroptosis.

Ferroptosis is a redox-driven type of regulated cell death program arising from maladaptation of three metabolic pathways: glutathione homeostasis, iron handling and lipid peroxidation. Though GSH/Gpx4 is the predominant system detoxifying phospholipid hydroperoxides (PLOOH) in mammalian cells, recently Gpx4-independent regulators of ferroptosis like ferroptosis suppressor protein 1 (FSP1) in resistant cancer lines and iNOS/NO• in M1 macrophages have been discovered. We previously reported that Pseudomonas aeruginosa (PA) utilizes its 15- lipoxygenase (pLoxA) to trigger ferroptotic death in epithelial cells by oxidizing the host arachidonoyl-phosphatidylethanolamine (ETE-PE) into pro-ferroptotic 15-hydroperoxy- arachidonyl-PE (15-HpETE-PE). Here we demonstrate that PA degrades the host GPx4 defense by activating the lysosomal chaperone-mediated autophagy (CMA). In response, the host stimulates the iNOS/NO•-driven anti-ferroptotic mechanism to stymie lipid peroxidation and protect GPx4/GSH-deficient cells. By using a co-culture model system, we showed that macrophage-produced NO• can distantly prevent PA stimulated ferroptosis in epithelial cells as an inter-cellular mechanism. We further established that suppression of ferroptosis in epithelial cells by NO• is enabled through the suppression of phospholipid peroxidation, particularly the production of pro-ferroptotic 15-HpETE-PE signals. Pharmacological targeting of iNOS (NO• generation) attenuated its anti-ferroptotic function. In conclusion, our findings define a new inter-cellular ferroptosis suppression mechanism which may represent a new strategy of the host against P. aeruginosa induced theft-ferroptosis.

Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death.

Ferroptotic death is the penalty for losing control over three processes-iron metabolism, lipid peroxidation and thiol regulation-that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NO•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells, whereas NO• donors empower resistance of M2 cells to ferroptosis. In vivo, M1 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (ETE)-PE intermediates and oxidatively truncated species by NO• donors and/or suppression of NO• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.