Elsevier

Sleep Medicine Reviews

Volume 52, August 2020, 101309
Sleep Medicine Reviews

Clinical Review
Sleep apnoea and endothelial dysfunction: An individual patient data meta-analysis

https://doi.org/10.1016/j.smrv.2020.101309Get rights and content

Summary

We performed an individual patient data meta-analysis to investigate the association between obstructive sleep apnoea (OSA) severity and the reactive hyperaemia index (RHI) measured by peripheral arterial tonometry (PAT), a validated measurement of endothelial function, and a strong predictor of late cardiovascular (CV) events. Patients from 12 studies underwent PAT and overnight polysomnography or respiratory polygraphy for suspected OSA. Endothelial dysfunction was defined by a log-transformed RHI<0.51. Subgroup analyses were performed to investigate this relationship in specific populations. Among 730 patients without overt CV disease, 387 (53.0%) had severe OSA (apnoea-hypopnea index ≥30) and 164 (22.5%) exhibited endothelial dysfunction. After adjustment for age, gender, diastolic blood pressure, obesity, diabetes and chronic obstructive pulmonary disease, endothelial dysfunction was associated with severe OSA (odds ratio, OR [95% confidence interval]: 2.27 [1.12–4.60]; p = 0.02), and nocturnal hypoxemia defined by >20 min with oxygen saturation <90% (OR: 1.83 [1.22–2.92]; p = 0.004) or mean oxygen saturation <92% (OR: 1.52 [1.17–1.96]; p = 0.002). On subgroup analyses, the association between severe OSA and endothelial dysfunction was not significant in patients with hypertension, obesity and/or diabetes. Among adults without overt CV disease, severe OSA is independently associated with an increased risk of endothelial dysfunction that may predispose to late CV events.

Introduction

The endothelium plays important roles in modulating vascular tone by synthesizing and releasing endothelium-derived relaxing factors. Endothelial dysfunction caused by reduced production or action of endothelium-derived relaxing factors is considered to be an initial step toward cardiovascular (CV) disease in at-risk patients [1,2]. In the clinical setting, non-invasive evaluation of peripheral endothelial function constitutes an excellent surrogate marker for prediction of incident CV events [2]. Many studies have correlated endothelial dysfunction with CV risk in patients with risk factors such as systemic hypertension, diabetes mellitus, dyslipidaemia and obesity/insulin resistance [3]. A recent systematic review and meta-analysis showed that brachial artery flow-mediated dilation (FMD), and reactive hyperaemia index (RHI) determined by peripheral arterial tonometry (PAT) significantly predicted CV events, with similar reliability [4]. From a technical viewpoint, PAT offers the advantages of being completely non-invasive, easy to perform, and less prone to inter-observers variability and thus more reproducible than FMD [3,5].

Evidence from population- and clinic-based cohort studies supports a causal association between obstructive sleep apnoea (OSA) and the incidence of CV diseases, including hypertension, coronary heart disease, arrhythmia, heart failure, and stroke [6,7]. Endothelial dysfunction is considered to be a key trigger mechanism linking OSA and its hypoxia-related consequences with CV morbidity [8,9]. Given the marked heterogeneity of OSA in terms of clinical phenotypes [10,11], comorbidities and health outcomes [12], endothelial function could be used as a predictive tool to more accurately identify OSA patients with preclinical vascular disease at high risk of subsequent CV events. However, the evidence of the relationship between OSA and endothelial dysfunction needs to be strengthened, taking into account indices of sleep-disordered breathing severity and influencing covariates. Previous systematic reviews and meta-analyses in the field have included heterogeneous studies with a limited description of comorbid conditions with a potential important contribution to OSA-associated CV risk, such as hypertension and metabolic disorders [9,∗[13], [14], ∗[15]]. Furthermore, the majority of these studies were small single-centre studies evaluating endothelial function by FMD which is subject to intra- and inter-operator variability [3,5]. Approaches using individual patient data meta-analysis (IPDMA) do not aggregate summary data, but address study questions by including actual patient data from different data sources [16]. Using individual data of OSA indices of severity overcomes limitations related to the selective cut-offs used in previous publications and allows specific subgroup analyses. Individual patient data concerning confounders allow more reliable adjustment.

The aim of this IPDMA was to investigate with appropriate adjustment for confounders the relationship between OSA severity indices and RHI, a validated and reproducible measurement of endothelial function.

Section snippets

Methods

We pooled individual data from patients with clinical suspicion of OSA and no overt CV disease involved in 12 separate studies (seven randomized controlled trials and five observational studies) initiated between 2007 and 2013 by the Departments of Respiratory and Sleep Medicine of Angers and Grenoble University Hospitals. Only data obtained at the baseline evaluation of interventional and observational studies were included in the present IPDMA. Patients with technical failure of PAT and/or

Results

The details of the 12 studies included in the IPDMA are presented in the online supplement (Table S1). Seventy-two of the 802 eligible patients were excluded due to history of CV disease (n = 42) or PAT technical failure (n = 30). Our final sample size comprised 730 patients with clinical suspicion of OSA and no overt CV disease (Fig. 1). Patient characteristics according to the original studies are presented in the online supplement (Table S2). As shown in Table 1, the prevalence of

Discussion

To the best of our knowledge, this is the first IPDMA evaluating the association between OSA severity and endothelial dysfunction with appropriate adjustment for confounding factors. Our study included a relatively large sample of typical OSA patients, predominantly male, without overt CV disease. All data were obtained using standard operating procedures and a validated measurement of endothelial function with low inter-observer variability. We found that both severe OSA and nocturnal

Funding

JLP, IJD, MJF and RT are supported by a research grant from the French National Research Agency (ANR-12-TECS-0010), in the framework of the “Investissements d’avenir” program (ANR-15-IDEX-02) and the “e-health and integrated care” Chair of excellence from the Grenoble Alpes University Foundation.

Conflicts of interest

FGag reports personal fees from AIR LIQUIDE SANTE, CIDELEC, RESMED, SEFAM, outside the submitted work; non-financial support from AIR LIQUIDE SANTE, ASTEN SANTE, SEFAM, outside the submitted work.

JLP reports grants from AGIRADOM, AIR LIQUIDE FOUNDATION, PHILIPS RESPIRONICS, RESMED, SEFAM, VITALAIR, outside the submitted work; personal fees from AGIRADOM, ITAMAR, JAZZ PHARMACEUTICALS, PHILIPS RESPIRONICS, RESMED, SEFAM, outside the submitted.

VB, RT, WT, RA, Mathieu Berger, FGou, MJF, IJD, SL,

Acknowledgements

We are grateful to the co-authors who made this meta-analysis possible by accepting to share their individual patient data.

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