rivaroxaban and Sleep-Apnea--Obstructive

Patients with chronic kidney disease (CKD) have a high prevalence of atrial fibrillation (AF). Stroke in patients with CKD and AF is frequent, and is usually more severe than in the absence of CKD. Current European Society of Cardiology guidelines recommend oral anticoagulant therapy in order to reduce thromboembolic risk in AF patients in general, and also in the presence of CKD, excluding however stage 4 and dialysis (stage 5) patients. Warfarin and other vitamin K antagonists are still the most frequently used drugs in these settings, despite the high bleeding risk. In the United States, the non-vitamin K antagonist oral anticoagulants, especially apixaban, are here used off-label, despite the absence of strong evidences of efficacy and safety. Several clinical trials are ongoing, and further evidence is needed before non-vitamin K antagonists can be recommended in these patients.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Diabetes Complications; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Hypertension; Male; Middle Aged; Off-Label Use; Prevalence; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency, Chronic; Risk Factors; Rivaroxaban; Sex Factors; Sleep Apnea, Obstructive; Stroke; Thiazoles; Thromboembolism

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