rivaroxaban and Hypoxia

Patients with sleep-disordered breathing exhibit intermittent hypoxia that causes increased oxidative stress, accelerates atherosclerosis, and pulmonary hypertension, resulting in life-threatening arrhythmias and congestive heart failure. Hypoxic stress caused by intermittent hypoxia might be involved in the pathophysiology of many cardiovascular diseases, especially those involving atrial fibrillation, for which anti-coagulant therapy may be recommended. In this study, the inhibition of proteinase-activated receptor (PAR) 1/2 significantly reduced oxidative stress and fibrosis while suppressing the activation of MAPK or Smad pathways and the gene expression of molecules responsible for the pathways in the myocardium, consequently attenuating hypoxia-mediated cardiomyocyte hypertrophy. These findings suggest that the inhibition of PAR 1/2 could be a novel potential treatment option to prevent cardiac remodeling in patients with sleep apnea syndrome and atrial fibrillation or chronic thromboembolic pulmonary hypertension.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Cardiovascular Diseases; Disease Models, Animal; Humans; Hypertension, Pulmonary; Hypoxia; Mice, Inbred C57BL; Molecular Targeted Therapy; Oxidative Stress; Rats; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; Sleep Apnea Syndromes; Ventricular Remodeling

We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist therapy. These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms.

Topics: Acute Disease; Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Betacoronavirus; Biomarkers; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Testing; Cytokine Release Syndrome; Enoxaparin; Female; Fibrin Fibrinogen Degradation Products; Humans; Hypoxia; Male; Methylprednisolone Hemisuccinate; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Rivaroxaban; SARS-CoV-2; Tomography, X-Ray Computed; Treatment Outcome

Patients with obstructive sleep apnea (OSA) have a high prevalence of atrial fibrillation (AF). Rivaroxaban, a coagulation factor Xa inhibitor, has recently been reported to show pleiotropic effects. This study investigated the influence of rivaroxaban on cardiac remodeling caused by intermittent hypoxia (IH). Male C57BL/6J mice were exposed to IH (repeated cycles of 5% oxygen for 1.5 min followed by 21% oxygen for 5 min) for 28 days with/without rivaroxaban (12 mg/kg/day) or FSLLRY, a protease-activated receptor (PAR)-2 antagonist (10 μg/kg/day). IH caused endothelial cell degeneration in the small arteries of the right atrial myocardium and increased the level of %fibrosis and 4-hydroxy-2-nonenal protein adducts in the left ventricular myocardium. IH also increased the expression of PAR-2 as well as the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and nuclear factor-kappa B (NF-κB) were increased in human cardiac microvascular endothelial cells. However, rivaroxaban and FSLLRY significantly suppressed these changes. These findings demonstrate that rivaroxaban attenuates both atrial and ventricular remodeling induced by IH through the prevention of oxidative stress and fibrosis by suppressing the activation of ERK and NF-κB pathways via PAR-2. Treatment with rivaroxaban could potentially become a novel therapeutic strategy for cardiac remodeling in patients with OSA and AF.

Topics: Animals; Atrial Fibrillation; Cells, Cultured; Endothelial Cells; Factor Xa Inhibitors; Fibrosis; Hypoxia; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Molecular Targeted Therapy; Myocardium; NF-kappa B; Oligopeptides; Oxidative Stress; Receptor, PAR-2; Rivaroxaban; Sleep Apnea, Obstructive; Ventricular Remodeling