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.

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T. Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters. Am J Physiol Heart Circ Physiol 307: H1626 -H1633, 2014. First published October 3, 2014; doi:10.1152/ajpheart.00228.2014.-The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n ϭ 22) and cardiomyopathic (CM) hamsters (n ϭ 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e=, 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e= (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 m 2 ) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, ␤-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea. heart failure; intermittent hypoxia; oxidative stress; cardiomyopathic hamster; hydrogen gas SLEEP APNEA SYNDROME (SAS) is a breathing disorder characterized by recurrent episodes of apnea and/or hypopnea that increases the risk of cardiovascular morbidity and mortality (10,19,26). In persons with SAS, recurrent hypopnea/apnea leads to intermittent hypoxia (IH). The prevalence of SAS is much higher in patients with established cardiovascular disease, and central sleep apnea is associated with the more severe forms of heart failure (17), although the mechanisms underlying periodic breathing in patients with heart failure (HF) are complex and multifactorial.Oxidative stress arises because of an imbalance between free radical production and endogenous antioxidant defenses and is increased in patients with HF (4). Free radicals have also been linked to endothelial dysfunction and increased sympathetic tone (2, 16), whereas intravenous infusion of antioxidants reduces free radical levels and attenuates sympathetic activity in animal models of HF (32). It has been suggested that hydrogen gas produced in the large intestine by intestinal bacteria might scavenge hydroxyl radicals (6), and it was recen...

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