Effect of 5-year continuous positive airway pressure treatment on MMPs and TIMPs: implications for OSA comorbidities

Beatrix Simon,Bettina Gabor,Gyorgy Boszormenyi Nagy,Balazs Antus,Csilla Paska,Imre Barta,Eva Vizi

doi:10.1038/s41598-020-65029-6

Abstract

Continuous positive airway pressure (CPAP) treatment results in nearly complete remission of symptoms of obstructive sleep apnoea (OSA); however, its effect on OSA comorbidities including cardiovascular diseases remains contradictory. Here we investigated the short- and long-term effect of CPAP treatment on matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with severe OSA. Serum levels of 7 MMPs and 3 TIMPs were followed in OSA patients (n = 28) with an apnoea-hypopnoea index of ≥30 events/h at the time of diagnosis and at control visits (2 months, 6 months and 5 years) after initiation of fixed-pressure CPAP treatment. The first few months of CPAP therapy resulted in significant decrease of MMP-8 and MMP-9 levels (MMP-8: 146 (79–237) vs. 287 (170–560) pg/mL; MMP-9: 10.1 (7.1–14.1) vs. 12.7 (10.4–15.6) ng/mL, p < 0.05 for each at 2 months), while the rest of the panel remained unchanged as compared to baseline values. In contrast, at 5 years, despite of uninterrupted CPAP treatment and excellent adherence the levels of MMP-8, MMP-9 and TIMPs significantly increased (p < 0.05). Our data suggest that initiation of CPAP therapy leads to a decrease in the level of key MMPs in the short-term; however, this effect is not sustained over the long-term.

Highlights

Obstructive sleep apnoea (OSA) is characterized by repetitive, complete or partial collapse of the upper airways causing chronic intermittent hypoxia (CIH) and sleep fragmentation
Our study has demonstrated that Continuous positive airway pressure (CPAP) therapy in patients with severe obstructive sleep apnoea (OSA) results in a marked reduction in the serum levels of matrix metalloproteinases (MMPs)-8 and MMP-9 in the short-term, while at the same time it has lesser or no effect on the concentration of several other members of the MMPs and tissue inhibitors of metalloproteinases (TIMPs)
The most striking finding of our study was that the beneficial effect of CPAP on key MMPs implicated in the progression of atherosclerosis was not sustained over the long-term as by the end of the 5 year follow-up period, the levels of MMP-8, MMP-9 and TIMP-4 increased beyond even those detected at the time of OSA diagnosis

Summary

Introduction

Obstructive sleep apnoea (OSA) is characterized by repetitive, complete or partial collapse of the upper airways causing chronic intermittent hypoxia (CIH) and sleep fragmentation. Accumulating evidence suggests that the repetitive sequences of desaturation-reoxygenation lead to increased oxidative stress, sympathetic hyperreactivity, hypertension, progressive endothelial dysfunction, systemic inflammation, hormonal alterations, dyslipidemia and insulin resistance contributing to increased cardiovascular morbidity and mortality in patients with OSA1,2. A number of studies have been published on the short-term effects of CPAP on established CVD risk factors, for example on oxidative stress[14]. The development of OSA-induced CVDs, and in particular atherosclerosis, is a long and progressive process that is modulated by numerous OSA-independent factors such as systemic inflammation, sympathetic activity, obesity, diet and exercise[16]. It would be a mistake to extrapolate findings on the short-term effects of CPAP treatment on CVD risk factors and assume that they will be sustained over the long-term. The utility of CPAP in preventing CVDs in OSA has been questioned by a recent meta-analysis[17] that generated interesting pro and con arguments in this field[18,19]

Methods

Results

Conclusion