Abstract
BackgroundOSA increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes. However, a causal association is not firmly established and the mechanisms involved are poorly understood. The aims of this work were to determine whether chronic obstructive sleep apnea (OSA) induces an atrial pro-arrhythmogenic substrate and to explore whether mesenchymal stem cells (MSC) are able to prevent it in a rat model of OSA.MethodsA custom-made setup was used to mimic recurrent OSA-like airway obstructions in rats. OSA-rats (n = 16) were subjected to 15-second obstructions, 60 apneas/hour, 6 hours/day during 21 consecutive days. Sham rats (n = 14) were placed in the setup but no obstructions were applied. In a second series of rats, MSC were administered to OSA-rats and saline to Sham-rats. Myocardial collagen deposit was evaluated in Picrosirius-red stained samples. mRNA expression of genes involved in collagen turnover, inflammation and oxidative stress were quantified by real time PCR. MMP-2 protein levels were quantified by Western Blot.ResultsA 43% greater interstitial collagen fraction was observed in the atria, but not in the ventricles, of OSA-rats compared to Sham-rats (Sham 8.32 ± 0.46% vs OSA 11.90 ± 0.59%, P < 0.01). Angiotensin-I Converting Enzyme (ACE) and Interleukin 6 (IL-6) expression were significantly increased in both atria, while Matrix Metalloproteinase-2 (MMP-2) expression was decreased. MSC administration blunted OSA-induced atrial fibrosis (Sham + Saline 8.39 ± 0.56% vs OSA + MSC 9.57 ± 0.31%, P = 0.11), as well as changes in MMP-2 and IL-6 expression. Interleukin 1-β (IL-1β) plasma concentration correlated to atrial but not ventricular fibrosis. Notably, a 2.5-fold increase in IL-1β plasma levels was observed in the OSA group, which was prevented in rats receiving MSC.ConclusionsOSA induces selective atrial fibrosis in a chronic murine model, which can be mediated in part by the systemic and local inflammation and by decreased collagen-degradation. MSCs transplantation prevents atrial fibrosis, suggesting that these stem cells could counterbalance inflammation in OSA.
Highlights
obstructive sleep apnea (OSA) increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes
It remains unknown whether chronic exposure to recurrent apneas can reach to develop atrial fibrosis, explaining the higher prevalence and incidence of AF observed in OSA patients
No significant differences between both groups were found in heart weight (Sham 1.21 ± 0.02 g. vs OSA 1.14 ± 0.03 g, P = 0.08), right ventricle (RV) free wall thickness (Sham 938 ± 55 μm vs OSA 876 ± 65 μm, P = 0.49), interventricular septum (IVS) thickness (Sham 2234 ± 162 μm vs OSA 2069 ± 190 μm, P = 0.54) or left ventricle (LV) free wall thickness (Sham 2427 ± 178 μm vs OSA 2300 ± 190 μm, P = 0.64)
Summary
OSA increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes. The aims of this work were to determine whether chronic obstructive sleep apnea (OSA) induces an atrial pro-arrhythmogenic substrate and to explore whether mesenchymal stem cells (MSC) are able to prevent it in a rat model of OSA. Patients with obstructive sleep apnea (OSA) show both a high prevalence [1] and incidence [2] of atrial fibrillation (AF). It remains unknown whether chronic exposure to recurrent apneas can reach to develop atrial fibrosis, explaining the higher prevalence and incidence of AF observed in OSA patients. Cell-based therapies emerge as an attractive alternative to classic pharmacological treatments for the prevention of such remodeling, thereby reducing AF occurrence and progression. The knowledge on the therapeutic role of MSC in OSA models is very limited [18], there is evidence that stem cells possess anti-inflammatory properties that mitigate the early inflammatory response [11]
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