Introduction
Obstructive sleep apnoea (OSA) is a sleep-related breathing disorder characterized by the repeated collapse of the upper airway during sleep, leading to intermittent hypoxia, intrathoracic pressure swings, and fragmented sleep [
1,
2]. OSA increases the risk of cardiovascular diseases, such as hypertension and coronary artery disease, partly due to changes in the autonomic nervous system, particularly upregulated sympathetic nerve activity [
3].
Mandibular advancement splint (MAS) is an effective treatment for OSA and works by increasing upper airway patency and reducing collapsibility [
4]. Currently, MAS is the recommended therapy for mild-moderate OSA and severe OSA when continuous positive airway pressure (CPAP) treatment is not tolerated [
5]. Evidence suggests that health outcomes, at least in the short term, are comparable between MAS and CPAP therapy [
6]. Randomized controlled trials of MAS treatment have demonstrated improved 24-h mean arterial blood pressure, which is more pronounced in hypertensive patients and those with resistant hypertension [
7,
8]. However, the effects of MAS therapy on other intermediary cardiovascular markers, such as cardiac autonomic function, remain poorly understood [
9], highlighting the need for further research on its potential to reduce cardiovascular risk.
Heart rate variability (HRV) analysis can be used non-invasively to evaluate beat-to-beat changes in cardiac autonomic control, which is particularly valuable for evaluating the relative activity of sympathetic and parasympathetic cardiac modulation [
10]. OSA is associated with an HRV profile indicative of sympathetic predominance, which is a hallmark of hypertension, a major risk factor for cardiovascular disease [
11]. Therefore, we aimed to use HRV to assess cardiac autonomic function following MAS therapy. We hypothesized that cardiac autonomic function would improve following successful MAS treatment i.e. that there would be a reduction in sympathetic and an increase in parasympathetic HRV markers.
Discussion
This study investigated the effect of MAS treatment on cardiac autonomic function in patients with OSA. Our hypothesis was that successful MAS treatment would result in increased parasympathetic and reduced sympathetic cardiac autonomic modulation. The findings revealed a novel correlation between successful MAS therapy and lengthened NN intervals, a marker of improved cardiac autonomic adaptability [
17]. Specifically, each unit of reduction in AHI was associated with a 2.21 unit increase in NN interval length, and a similar trend towards higher pNN50 with improved AHI. The lengthened NN interval observed resulted from increased cardiac vagal modulation, which reflected improved cardiac autonomic adaptability and may have implications for reducing cardiovascular risk [
17].
Of the five similar studies undertaken [
18], only one study has reported nocturnal vagal predominance after MAS use [
19]. The authors showed in their retrospective study that after 3 months of MAS use (
N = 58), patients demonstrated improved cardiac autonomic adaptability through increases in average NN, normalized HF power, and SDNN and reduced normalized LF power [
19]. In addition, other studies have reported an increase in daytime normalized HF power after short-term MAS use, albeit using small sample sizes (
N = 10) and only during a controlled breathing protocol, rather than normal breathing [
19,
20]. In the other studies investigating changes to HRV markers after MAS, no changes to sympathetic or vagal markers were found [
21,
22]. In their randomized crossover trial, Dal-Fabbro and colleagues [
21] showed that compared with placebo oral appliance, global HRV marker, TP, was significantly lower, with no differences found between MAS and CPAP treatment periods. Collectively, these findings suggest that MAS use may result in improved cardiac autonomic adaptability, though different studies have yielded different conclusions.
Clinically, MAS use is hindered by its varying degrees of efficacy whereby around one-third of patients completely resolve OSA with MAS treatment, one-third will have a demonstrated halving of their OSA severity, and one-third will demonstrate minimal effect [
23]. Therefore, patient responsiveness to MAS therapy must be considered when evaluating treatment effect on cardiac autonomic function. In our study, improvement in vagally mediated HRV markers was only observed after considering responsiveness to MAS treatment (i.e., those with a greater change in AHI). We found a trend towards increased pNN50 with improved AHI. Similar subgroup analyses of treatment responders (
n = 34, defined as, > 50% reduction in AHI and AHI < 20/h after treatment) identified significant increases in average NN and normalized HF power, accompanied by reductions in TP, VLF, LF, LF:HF ratio, and normalized LF power after MAS treatment [
19]. In contrast, no significant changes in cardiac autonomic function were observed in the non-responder group (
n = 24), defined as those with a < 50% reduction in AHI and AHI > 20/h following treatment [
19]. Taken together, these two investigations suggest responders to MAS treatment experience a marked shift towards parasympathetic predominance in sympathovagal balance, characteristic of improved cardiac autonomic regulation. However, the lack of uniformity in results across all MAS treatment trials suggests that responsiveness to MAS therapy is only one factor contributing to improved cardiovascular health.
Despite an inextricable link between OSA and cardiovascular risk, the largest randomized study to date with a 3.7-year follow-up period investigating OSA treatment failed to demonstrate any improvement in hard cardiovascular endpoints [
24]. A significant limitation in this trial was poor treatment adherence to CPAP, which was only 3.3 h/night in a population with cardiovascular disease [
24]. While MAS therapy is generally less efficacious than CPAP, its higher treatment adherence makes both treatment modalities equally effective [
23]. The main set-back to ours and other MAS treatment trials has been a lack of access to technologies to objectively record daily adherence. Therefore, future MAS trials should consider the effects of treatment responsiveness and objective daily adherence when evaluating cardiovascular risk.
HRV is a useful tool to monitor the cardiac autonomic benefits of OSA treatment, yet there is substantial heterogeneity among treatment trials [
18]. Differences in HRV indices used and HRV sensitivity to external factors affecting HRV measurements are observed. Not only do methodologies vary between whether or not HRV is measured during daytime, nighttime, or over 24 h [
18]. Some studies used single 5-min segments to represent changes that occur over whole sleep stages [
21], while others used a minimum number of beats per tachogram [
25], or limited their nocturnal analyses to specific times irrespective of sleep stages [
19]. This is problematic as time domain analysis of HRV is highly influenced by the condition and duration of the recording [
10]. Routine recording of ECG during polysomnography makes assessment of HRV during sleep a widely used and easily accessible method for measuring cardiac autonomic function. However, disordered respiration experienced by patients with OSA reduces the sensitivity of HRV as a tool for evaluating the effectiveness of OSA therapy on global measures of HRV [
10]. We addressed this concern by excluding ECG segments with respiratory events, ectopic beats, and other cardiac arrhythmias. In order to increase sensitivity of our HRV measure, we also adopted a methodology of averaging HRV markers across the entire PSG-derived ECG using a shifting window of 2 min, and generating HRV measurements for the N2 sleep stage, as is common practice [
15]. However, our study could have benefitted from longer duration of data collection. Using 24-h Holter monitoring to assess the SDNN as a marker of global HRV is preferable for HRV assessment, as it can better account for metabolic and circadian variability, which are strongly associated with cardiovascular risk [
10].
In some patients, MAS treatment can alter nocturnal cardiac autonomic activity. Multiple studies have shown that MAS treatment may enhance vagally mediated markers, thereby improving cardiac autonomic adaptability. However, research in the field of MAS is hampered by various challenges. As previously highlighted, the lack of objective daily usage data is a major limitation to this and other similar studies. While some studies have provided preliminary data on average usage using objective adherence monitors for up to 1 year of treatment, these studies were small and did not evaluate cardiovascular outcomes. In contrast, our study had a relatively large sample size and captured a more comprehensive and accurate measure for cardiac autonomic function by averaging HRV markers over the entire ECG. However, our study did use data sets from three separate treatment trials and adherence was not measured uniformly across these studies. Therefore, we were unable to provide objective or subjective measures of adherence.
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