Effect of obstructive sleep apnoea on severity and short-term prognosis of acute coronary syndrome

Introduction

Obstructive sleep apnoea (OSA) is a common disease that affects 3–7% of the general population [1, 2]. Sleep apnoea is caused by the collapse of the upper airway during sleep, which leads to transient asphyxia. OSA is associated with an increased risk of fatal and nonfatal cardiovascular events [3] and effective continuous positive airway pressure (CPAP) treatment reduces the incidence of hypertension and cardiovascular events [4]. The consequences of OSA are largely mediated by chronic intermittent hypoxia and sleep fragmentation, which may contribute to the pathogenesis of cardiovascular disease in patients with sleep apnoea [5]. Intermittent episodes of hypoxia and arousal cause an increase in sympathetic activity [6] and sudden changes in systemic blood pressure [7], which contribute to the development of myocardial hypertrophy, cardiac arrhythmias and death. OSA is associated with abnormalities in cardiac autonomic and electrophysiological factors, including heart rate variability, the duration of the QT interval, baroreflex function, and chemoreceptor sensitivity. Serious and potentially fatal arrhythmias occur during sleep in patients with OSA [8] and are attenuated by effective treatment with CPAP [9]. Subjects with OSA are at increased risk of sudden death from cardiac causes during sleeping hours [10].

These pathogenic factors in OSA patients may play an aggravating role in the severity of acute myocardial infarction (AMI) and the short-term prognosis of patients. Nevertheless, a cardioprotective role of OSA in the context of AMI, via ischaemic preconditioning, has also been postulated. This latter hypothesis implies the activation of adaptive mechanisms, such as the increased recruitment of proliferative and angiogenic endothelial progenitor cells [11]. Furthermore, patients with OSA reportedly exhibit less severe cardiac injury during an acute nonfatal myocardial infarction compared with patients without OSA [12].

Due to this contradictory evidence, we performed an observational study to evaluate the impact of OSA on the severity and short-term prognosis of patients with acute coronary syndrome (ACS). The objective of the study was to compare the ejection fraction, Killip class, number of diseased vessels, peak troponin, length of hospitalisation, number of complications, and mortality rate of a cohort of ACS patients with and without OSA.

Results

We included 218 patients with an AHI ⩽15 events·h⁻¹ (control group) and 213 patients with an AHI >15 events·h⁻¹ (OSA group). OSA patients were slightly, but significantly, older than the controls (table 1) (p=0.0002). Hypertension was more prevalent in patients from the OSA group (table  1) (p=0.0004), who also exhibited an increased use of diuretics and calcium antagonists (table  1) p=0.02 and p=0.0009, respectively). Additionally, OSA patients exhibited a higher BMI and were less likely to be current or former smokers than control patients (table  1) (p<0.00001 and p=0.04, respectively). 95% of OSA patients and 91% of controls underwent peripheral coronary intervention, which included 42% and 44% undergoing primary peripheral coronary intervention, respectively.

With respect to ACS severity, the percentages of patients with Killip classes II–IV and ⩾3 diseased vessels were higher in the OSA group (table 2) (p=0.03 and p=0.006, respectively). For OSA patients, we observed that the mean ejection fraction was lower, whereas the mean peak troponin was higher (table 2) (p=0.04 and p=0.005, respectively). However, the analysis adjusted for smoking, age, BMI and hypertension revealed that only the peak troponin levels were statistically significant (table 2) (p=0.03).

With respect to the ACS short-term prognosis, the mean length of stay in the coronary care unit was higher in the OSA group even after adjustment (table 3) (p=0.01 and p=0.03). Nevertheless, the length of hospitalisation, number of complications and mortality rate during hospitalisation were similar between the groups.

To further investigate the strength of the association of ACS severity-related variables with OSA severity, we classified the patients into four groups according to AHI Q1–4. The results confirmed that the peak troponin levels increased with each AHI Q, even after adjustment (table 4 and fig. 2) (p=0.0003 and p=0.002). Additionally, this analysis revealed that the number of diseased vessels was higher for the most severe OSA group (AHI >27.2 events·h⁻¹), even after adjustment (table 4 and fig. 2) (p=0.001 and p=0.04). Moreover, the odds ratios for three or more diseased vessels (with respect to one vessel) were 2.07, 2.08 and 2.36, when comparing individuals above AHI Q1–3 with respect to those below Q2–4, respectively (table S1, p=0.11, p=0.006 and p=0.04). However, when analysing the association between ACS short-term prognosis with OSA severity, there was no statistically significant association (table 5).

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FIGURE 2

Association between acute coronary syndrome severity variables and obstructive sleep apnoea. a) Frequency distribution for the number of diseased vessels in apnoea–hypopnoea index (AHI) quartiles (Q). b) Peak troponin mean values for AHI Q1–4, segments represent one standard deviation. The analysis was adjusted by smoking, age, body mass index, and hypertension. The adjusted p-values in table 4 are shown.

Finally, we determined an optimal threshold for each ACS severity outcome to discriminate between OSA and control patients with the goal of obtaining a more detailed description of this association. This analysis demonstrated a significant increase in the risk of an OSA patient to have a peak plasma troponin level >724.5 ng·L⁻¹ (table 6) (OR 2.59, p=0.02). This analysis also revealed a significant increase in the risk of an OSA patient to exhibit an ejection fraction lower than 51.5% (table 6) (OR 2.05, p=0.04) and a tendency to present with more than three diseased vessels (table 6) (OR 1.96, p=0.06).

Discussion

The results of this observational study suggest that OSA influences the severity of ACS and its short-term prognosis. OSA is related to an increase in peak plasma troponin level, a decrease in the ejection fraction, and an increase in the number of diseased vessels. After adjusting for smoking, hypertension, and BMI, only the peak plasma troponin levels remained significantly related to OSA. The OSA severity, evaluated by AHI, is related to the number of diseased vessels and the peak plasma troponin levels. Patients with OSA spent more time in the coronary care unit, although the length of hospitalisation was similar between patients with and without OSA.

Available data from clinic-based cohorts suggest that OSA is an independent risk factor for myocardial infarction and other coronary events [3, 18–21]. Furthermore, OSA worsens the long-term prognosis of ACS [22, 23]. Several pathogenic factors are proposed as intermediate mechanisms linking OSA with cardiovascular disease [5]. It has been described that systemic inflammation induced by chronic intermittent hypoxia may play a key role in atherogenesis in OSA patients [24]. These intermediate mechanisms can produce cardiac hyper-excitability and increase the sympathetic tone, oxidative stress and hypercoagulability, which could in turn increase the severity of ACS in OSA patients and worsen the prognosis of ACS. Additionally, chronic intermittent hypoxia increases the infarct size in animal models [25]. Also, the deleterious effects of sleep disordered breathing in infarct expansion and impaired healing of myocardial tissue and coronary artery plaque burden have been described [26–28]. The increased number of affected vessels and the increase in the peak plasma troponin levels in the group of patients with OSA could be associated with worse long-term prognosis. In contrast to our results, Lee et al. [29] reported similar severity in acute myocardial infarction in patients with and without OSA. This study also demonstrated that there was no significant association between OSA and impaired microvascular perfusion after primary percutaneous coronary intervention. Interestingly, Shah et al. [12] explained that patients with OSA exhibit less severe cardiac injuries during an acute nonfatal myocardial infarction compared with patients without OSA. The authors suggest a cardioprotective role of OSA during acute myocardial infarction induced by ischaemic preconditioning. Berger et al. [11] demonstrate that patients with AMI, who exhibit mild-to-moderate sleep disordered breathing, can activate adaptive mechanisms and may improve endothelial function and provide cardioprotection in the context of acute myocardial infarction. Additionally, organ autoregulation could be a mechanism implicated in maintaining a constant blood flow during fluctuations in its perfusion pressure in patients with ACS [30].

The strengths of our study include its multicentre design with a large number of patients. All participating centres performed the same methodology and the sleep study was performed with the same model of polygraph. Nevertheless, this study has several potential limitations. First, we excluded patients with the more severe ACS and worse prognosis (cardiogenic shock). Additionally, we excluded patients with daytime sleepiness who exhibited the most severe OSA. Nevertheless, the number of excluded patients for these causes was relatively low. Secondly, subjects in this study were predominantly male, therefore, the results cannot be extrapolated to females. Thirdly, the diagnosis is based on respiratory polygraphy, which could underestimate the severity of OSA. However, due to the critical situation of the patients, full polysomnography monitoring could be a stressful procedure for this high-risk patient group. Finally, the design of this study does not allow us to draw definitive conclusions and further randomised control trials on this topic will be necessary.