Clinical ReviewIs obstructive sleep apnoea causally related to arterial stiffness? A critical review of the experimental evidence
Introduction
Obstructive sleep apnoea (OSA) is increasingly being linked to excess cardiovascular disease (CVD). Longitudinal community cohort studies have shown both an increased risk for all-cause and cardiovascular mortality1, 2 as well as an increase in the incidence of coronary artery disease, heart failure3 and stroke.4 In the latter sleep heart health study (SHHS), the increased risk for developing these adverse outcomes that was attributable to OSA was independent of age, obesity, cholesterol and blood pressure levels.3, 4 However, whilst these cohort studies provide strong evidence of a causal link between OSA and CVD, there are still no prospective randomised trials of sufficient duration to demonstrate that treating OSA with continuous positive airway pressure (CPAP) reduces cardiovascular death or events. In reality, the vast majority of cardiovascular focussed studies in OSA has tended to examine intermediate markers of CVD risk, either in cross-sectional or interventional studies.
Arterial stiffness is increasingly being linked with poorer cardiovascular outcome and many studies now support its utility as an early independent predictor of cardiovascular mortality and morbidity. This review provides an overview of arterial stiffness in terms of its definition and measurement and what determinants and risk factors are linked to it. Also included is an overview of studies from the general cardiovascular literature that give a prognostic indication of arterial stiffness independent of traditional risk factors. This will enhance understanding of the OSA studies that have assessed arterial stiffness which follow.
Section snippets
Definitions of arterial stiffness
The stiffness of the artery wall can be calculated by applying a stress to the artery and measuring the resultant strain. The ratio of stress to strain (Young's modulus) gives the stiffness of the material. Due to the complexities in accurately measuring the stress and strain in arteries both in-vivo and ex-vivo, there have been many different indices developed that relate experimental measurements of parameters of vascular function to arterial wall stiffness. The definitions of these indices
Pressure dependency
All measures of arterial stiffness are pressure, or stress dependent as the arterial wall has a curvilinear stress/strain relationship, such that the wall stiffness increases with increasing distending pressure.8 Therefore comparisons must relate to the same distending pressure, or in population studies, account for blood pressure as a factor that influences arterial stiffness.
Various indices have been developed to correct for pressure, or to adjust for the exponential relationship between
Measurements utilising pressure and diameter
The most direct in-vivo measurement of arterial stiffness relates change in arterial diameter (a measure of strain) to change in arterial pressure (a measure of stress) at the same site. By measuring pressure and diameter, stiffness (Table 1) can be expressed as distensibility, compliance, or the Peterson's or Young's elastic modulus. Pressure and diameter measurements can be obtained invasively with a combined ultrasound and manometer catheter system.44 Whilst similar diameter measurements can
Prognostic value of arterial stiffness
Studies addressing the prognostic value of arterial stiffness have used measures of aortic PWV as well as pulse pressure and derived parameters such as augmentation index. There is now considerable evidence to indicate that carotid–femoral PWV is a strong predictor of fatal and non-fatal cardiovascular events.54 Early studies56, 57, 58 have been supplemented by more recent studies and meta analyses showing a strong and independent predictive power of aortic PWV in hypertension, coronary artery
OSA and arterial stiffness
The previous sections give an overview of arterial stiffness with respect to definitions, measurement techniques, determinants and prognostic data. Many of the determinants including increased blood pressure,70 sympathetic activity71, 72 and endothelial dysfunction73 have been causatively linked to OSA. The remainder of this review summarises the cross-sectional and CPAP intervention studies that have assessed arterial stiffness in OSA. The study designs in relation to the origin of the
Study designs
Table 3 shows the cross-sectional (and case-control) studies linking OSA with arterial stiffness. The majority of studies recruited participants from sleep clinic patients,53, 75, *76, 77, 78, 79, *80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 however there are two community based studies*92, 93 and two studies that specifically recruited patients from speciality clinics who had a primary diagnosis of hypertension94 or the metabolic syndrome (MS)95 and in both studies, OSA was subsequently
Study designs
Table 4 shows the 12 CPAP intervention studies linking OSA with arterial stiffness. There were only two studies which incorporated a control group in the study design and both were randomised trials.*102, *103 Most of the studies included OSA that was at least moderate (AHI ≥ 15) with a majority having a mean AHI in the severe range (AHI ≥ 30). The treatment duration of most studies exceeded 1 mo, however one study involved withdrawal of CPAP for seven nights104 whilst a second involved CPAP
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