Effects of moderate-to-severe obstructive sleep apnea on the clinical manifestations of plaque vulnerability and the progression of coronary atherosclerosis in patients with acute coronary syndrome

Abstract

Aims

It is unclear whether obstructive sleep apnea (OSA) increases the recurrence of acute coronary syndrome (ACS) in patients with acute myocardial infarction (MI). We hypothesized that moderate-to-severe OSA increased the number of adverse cardiovascular events in patients who underwent primary percutaneous coronary intervention (PCI).

Methods and results

This study included 272 patients with acute MI. Polysomnography at first admission determined that 124 patients suffered from moderate-to-severe OSA. The main study outcome measures were cardiac death, recurrence of ACS, and re-admission for heart failure. Major adverse cardiac events (MACEs) were defined as composite end points of individual clinical outcomes. Follow-up coronary angiograms were obtained in 222 patients. PCI-related measures were target vessel revascularization and newly necessitated PCI for progressive lesions. The moderate-to-severe OSA patients had increased ACS recurrence and MACEs compared with patients with mild OSA or without sleep apnea (16% vs. 7%, p = 0.014; 22% vs. 11%, p = 0.014, respectively). PCI for progressive lesions was also higher in the moderate-to-severe OSA patients (28% vs. 15%, p = 0.015). Cox regression analysis showed that moderate-to-severe OSA was an independent predictor of ACS recurrence (hazard ratio = 2.30, p = 0.040). In addition, moderate-to-severe OSA was an independent predictor of PCI for progressive lesions, with a hazard ratio of 2.38 (p = 0.015).

Conclusions

Moderate-to-severe OSA increased the risk of ACS and the incidence of PCI for progressive lesions. Increased plaque vulnerability might be related to these clinical manifestations.

Introduction

Cumulative epidemiological evidence of primary prevention suggests that untreated obstructive sleep apnea (OSA) increases the risk of cardiovascular mortality or morbidity in patients not presenting with cardiovascular disease.^1–4 This suggests that severe OSA patients have the highest risk for the occurrence of cardiovascular events. In 408 patients with stable angina pectoris, sleep apnea (including both OSA and central sleep apnea (CSA) patients) was positively correlated with a composite end point of death, cerebrovascular events and myocardial infarction (MI). The worst clinical outcomes were mainly driven by increased cerebrovascular events. The incidence of MI was comparable between sleep apnea and control patients.⁵ Cassar et al. assessed 371 OSA patients who underwent percutaneous coronary intervention (PCI) and revealed that untreated OSA was associated with increased cardiac death compared with treated OSA. However, the incidence of major cardiac events, defined as severe angina, MI, revascularization or cardiac death, was not different between treated and untreated OSA patients.⁶ Other small follow-up studies reported inconsistent results in terms of the association between OSA and acute coronary syndrome (ACS).^7–9 Prevention of ACS development is the most important therapeutic strategy for coronary artery disease. In addition to modifying conventional risk factors, the identification of novel therapeutic targets could be essential. However, whether OSA plays a role in ACS occurrence remains unclear. OSA exerts unfavorable effects on the cardiovascular system, including increased oxidative stress, higher sympathetic activity, increased platelet activity, repetitive hypoxia, and coronary microvascular dysfunction.^10–13 Therefore, it is likely that OSA enhances plaque vulnerability and the progression of coronary atherosclerosis.

In the present study, we hypothesized that moderate-to-severe OSA resulted in a higher risk of ACS recurrence, major adverse cardiac events (MACEs) and progression of coronary atherosclerosis. Two studies reported that untreated OSA resulted in an increased incidence of restenosis or target vessel revascularization (TVR).^14,15 However, whether OSA increased the incidence of PCI for de novo lesions remains unclear. Therefore, angiographic analysis was performed to examine the association between moderate-to-severe OSA and the incidence of TVR and PCI for progressive lesions. The effects of continuous positive airway pressure (CPAP) treatment on clinical outcomes were examined in a subset of patients with an apnea–hypopnea index (AHI) of ≥20 events/h.

Methods

In total, 391 patients admitted to Nagasaki Citizens Hospital with acute MI between January 2003 and December 2009, who underwent primary PCI within 12 h of onset and had been discharged alive, were initially considered for enrollment in the present study. Acute MI was defined as ischemic symptoms lasting for ≥30 min with ST-segment elevation or depression (≥1 mm), an increase in creatine kinase to twice the normal upper levels and an elevation of cardiac troponin T levels (≥0.1 ng/ml). All eligible patients were recommended to undergo polysomnography before discharge on a systemic basis as an essential part of our study. The inclusion criteria were as follows: (1) adequate sleep studies without disrupted examination or missing sleep parameters, (2) polysomnographic findings showing AHI of <5 events/h, or AHI ≥5 events/h with predominant obstructive apnea–hypopnea, (3) at least one year of reported follow-up, and (4) written informed consent was obtained. On the basis of these criteria, 119 patients were excluded from the study, as illustrated in Figure 1. This study complied with the Helsinki Declaration and was approved by all relevant committees at our institution. Written informed consent was obtained from all patients.

Polysomnography

Full polysomnography was performed in all patients using an 18-channel polysomnograph (Alice 3 or 4 Diagnostics system, Chest MI, Inc., Tokyo, Japan) between 14 and 21 days after the first admission. Electroencephalograms, electrooculograms and chin electromyograms were recorded to evaluate the stage of sleep. Sleep states and arousal were scored on the basis of standard criteria.^16,17 To determine the type of apnea, naso-oral airflow was measured using an oronasal thermistor and thoracoabdominal movements were measured using respiratory inductance plethysmography. Arterial oxyhemoglobin saturation was recorded using a finger pulse oximeter and electrocardiographic recordings were taken from a single lead. Apnea was defined as complete cessation of airflow lasting for ≥10 s. Hypopnea was defined as a ≥50% reduction in airflow lasting for ≥10 s that was associated with a 3% decrease in oxygen saturation or arousal. AHI was defined as the mean number of apnea plus hypopnea events per hour of sleep. OSA was defined as the absence of airflow despite respiratory movement or exertion. CSA was defined as the absence of both airflow and respiratory movement. Moderate-to-severe OSA was defined as AHI of ≥15.0 events/h, of which >50% were obstructive. Previous studies used various cutoff levels of AHI to define OSA.^5,6,15,18 As shown in Supplementary Tables 1 and 2 online, baseline clinical characteristics except for obesity and the incidence of long-term clinical outcomes were comparable between mild OSA patients with AHI of 5.0–14.9 events/h and those without sleep apnea, defined as AHI of <5.0 events/h. Thus, we used AHI of <15 events/h to define the reference patients. Moderate-to-severe OSA was defined as AHI of ≥15 events/h. All patients with AHI of ≥20 events/h underwent a second polysomnography with auto-titrating CPAP on the day after the first sleep study.

Follow-up data collection

Patient follow-up was performed after six months, one year and annually thereafter by co-authors who were blinded to the results of the sleep studies. Telephone interviews or reviews of medical records at our institution were used to determine clinical outcomes. All patients who experienced recurrent ACS or MACE were admitted to our hospital. The angiographic and PCI-related outcome measures were analyzed on the basis of both medical records and coronary arteriograms. When we could not contact patients or when follow-up medical records were unavailable, we contacted patients’ attending physician directly by mail. All causes of death were confirmed from medical records at the hospitals where patients died.

Clinical outcome measures included cardiac death, ACS recurrence and re-admission for heart failure. ACS was defined as acute MI or unstable angina. The diagnosis of unstable angina was based on new onset, worsening or resting angina associated with evidence of ST-segment elevation or depression without myocardial necrosis. Decompensated heart failure was diagnosed on the basis of the aggravation of dyspnea or edema associated with an increase in pulmonary congestion and cardiomegaly on chest radiographs, and an elevation of N-terminal pro-brain natriuretic peptide to ≥1.2-fold pre-discharge levels at first admission. MACEs were defined as composite end points of individual clinical outcomes including cardiac death, ACS recurrence and re-admission for heart failure. We recommended the implementation of CPAP treatment in all patients with AHI of ≥20 events/h because the Japanese Ministry of Health, Labor and Welfare has not approved the use of CPAP treatment for patients with AHI of <20 events/h. The effects of CPAP treatment on clinical outcomes were then analyzed. The compliance with CPAP treatment was evaluated using the time counter on the device.

Angiographic subanalysis was performed in 222 patients for whom at least one coronary arteriogram was obtained during the follow-up period. Coronary arteriography was performed because of the scheduled follow-up at six months and one year or the suspected recurrence of myocardial ischemia. The implementation of follow-up coronary arteriography was at the discretion of the attending cardiologist at initial admission. All PCIs during follow-up were based on a coronary diameter stenosis of ≥50% and evidence of myocardial ischemia confirmed by changes in ST segments during ischemic symptoms, myocardial perfusion imaging or fractional flow reserve. TVR was defined as repeat PCI for vessels successfully dilated at first admission. PCI-related outcome measures were TVR and newly necessitated PCI for progressed coronary lesions.

Definition of coronary risk factors

Patients who received medications for the treatment of hypercholesterolemia, hypertension and diabetes prior to the onset of acute MI were considered to have these risk factors. In patients who had not received medications for these risk factors, hypertension was defined as a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg on three separate occasions. Hypercholesterolemia was defined as a low-density lipoprotein cholesterol level of ≥140 mg/dl, calculated using the Friedewald formula. Diabetes was defined as a fasting blood glucose of ≥126 mg/dl on two separate occasions or a glycohemoglobin A1c level of ≥6.5%.

Statistical analysis

Continuous variables were expressed as median values and interquartile ranges because all continuous variables did not show normal distribution using the Shapiro–Wilk test. Comparisons of continuous variables were made between the moderate-to-severe OSA and reference patients using the Wilcoxon rank sum test. Dichotomous variables were expressed as counts with percentages and were compared using the χ² test or Fisher’s exact test when cells had counts of <5. Univariate Cox regression analyses were performed to examine the relationship between individual risk factors (including OSA, hypercholesterolemia, hypertension, diabetes, current smoking, BMI of ≥25 kg/m², age ≥75 years and male gender) and ACS recurrence and MACEs in all study patients and those without CPAP treatment, respectively. Time to event was calculated from the date of the first sleep study to the date that the individual clinical events first occurred. Multiple Cox regression analysis adjusted for risk factors was performed to identify independent risk factors for ACS recurrence and MACEs. ACS- and MACE-free survival estimates for all patients and those without CPAP treatment were calculated using the Kaplan–Meier method and compared using the log rank test. The effects of CPAP treatment on ACS recurrence in patients with AHI of ≥20 events/h were also compared using the Kaplan–Meier method. Statistical significance was defined as a two-sided p of <0.05. Data analyses were performed using SPSS statistical software, Version 19.0 (SPSS Inc., Chicago, IL, USA).

Results

In total, 124 patients (45.6%) fulfilled the criteria for moderate-to-severe OSA, and 148 had AHI of <15 events/h. Patient characteristics for the two groups are presented in Table 1. Median follow-up duration was not different between the two groups. The moderate-to-severe OSA patients were significantly older than the reference patients. No significant differences were observed between the two groups in terms of gender, previous angina within 24 h before onset, anterior infarct location and ST-segment elevation MI. Time to admission from the onset of symptoms, infarct size estimated by peak creatine kinase levels, and coronary angiographic findings were also comparable between the groups. A trend toward a higher incidence of initial Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 or 1 was detected in the reference patients; however, no difference was observed in the achievement of final TIMI flow grade 3. Coronary stents were implanted equally in the two groups. Conventional coronary risk factors, except for current smoking, were reported equally between the groups. Baseline medications at discharge after the first admission were also comparable.

Association between OSA and clinical outcomes

Total and cardiac death was comparable between the moderate-to-severe OSA patients and reference patients (12% vs. 9%, p = 0.371; 4% vs. 1%, p = 0.158, respectively). Cardiac death occurred in seven patients: five OSA and two reference patients. The causes of cardiac death were refractory heart failure in five patients (three OSA patients and two reference patients) and fatal MI in three patients (two OSA patients and one reference patient). The incidence of recurrent acute MI and unstable angina was higher in the moderate-to-severe OSA patients than in the reference patients (11% vs. 6%, p = 0.038; 6% vs. 3%, p = 0.179). As a result, the moderate-to-severe OSA patients showed a significantly higher incidence of ACS recurrence than the reference patients (16% vs. 7%, p = 0.014). Re-admission for heart failure was comparable between the groups (9% vs. 5%, p = 0.264). The incidence of MACEs was higher in the moderate-to-severe OSA patients than in the reference patients (22% vs. 11%, p = 0.014). Univariate Cox regression analysis showed that moderate-to-severe OSA and age ≥ 75 years were positively correlated with ACS recurrence and MACEs (Tables 2 and 3). Multivariate Cox regression analysis adjusted for eight risk factors suggested that moderate-to-severe OSA alone was an independent risk factor for ACS recurrence. In patients without CPAP treatment (n = 216), moderate-to-severe OSA was a significant risk factor for ACS recurrence and MACEs (Tables 4 and 5). As shown in Figure 2(a) and (b), Kaplan–Meier curves demonstrated that ACS- and MACE-free survival estimates for the moderate-to-severe OSA patients were significantly worse than those for the reference patients. As shown in Figure 2(c) and (d), when we excluded the 54 OSA patients undergoing CPAP treatment, more significant differences in ACS- and MACE-free survival estimates were observed between the groups. Importantly, the divergence of the event-free survival rate increased as the follow-up duration increased.

Association between OSA and PCI-related outcomes

Follow-up coronary arteriograms were obtained in 222 patients, and moderate-to-severe OSA was diagnosed in 100 patients (45%). The median follow-up duration was not different between the groups: 4.4 (interquartile range (IQR) 3.0−5.7) years vs. 3.9 (IQR 2.7–5.4) years, p = 0.094). One hundred and twenty-one vessels in the moderate-to-severe OSA patients and 146 vessels in the reference patients were successfully dilated using PCI at first admission. The mean number of target vessels per patient was comparable between the moderate-to-severe OSA and reference patients (1.2 ± 0.5 vs. 1.2 ± 0.5, p = 0.960). Coronary stents were equally implanted (97% vs. 98%, p = 0.652), and the use of drug-eluting stents was comparable between the groups (12% vs. 10%, p = 0.463). The incidence of TVR was not different between the groups (15% vs. 18%, p = 0.520). In contrast, the incidence of newly necessitated PCI for progressive lesions was higher in the OSA patients than in the reference patients (28% vs. 15%, p = 0.015). Multivariate Cox regression analysis adjusted for eight risk factors suggested that OSA and hypertension increased the risk of PCI for progressive lesions (hazard ratio of OSA: 2.38, 95% confidence interval (CI) 1.18–4.78, p = 0.015; hazard ratio of hypertension: 2.13, 95% CI 1.05–4.44, p = 0.043).

Effects of CPAP treatment on clinical outcomes

The effects of CPAP treatment were evaluated in 95 patients with AHI of ≥20 events/h. Fifty-six of these patients (59%) received CPAP treatment, and 39 patients refused or could not tolerate the treatment. Although CPAP treatment decreased the incidence of ACS recurrence and MACEs, these differences were not significant (9% vs. 23%, p = 0.056; 14% vs. 31%, p = 0.053, respectively). Similarly, ACS- and MACE-free survival estimates were not different between patients with and without CPAP treatment (log rank p = 0.129; p = 0.129, respectively).

Discussion

The main finding of this study was that moderate-to-severe OSA is an independent risk factor for ACS recurrence in patients who experienced acute MI. In patients without CPAP treatment, moderate-to-severe OSA increased the risk of both ACS recurrence and MACEs. In addition, moderate-to-severe OSA increased the risk of PCI for myocardial ischemia-related progressive coronary lesions. Our findings suggest that moderate-to-severe OSA might play a role in plaque vulnerability and lesion progression because other conventional risk factors were comparable between the two groups. The incidence of obesity has been reported to be similar between OSA and control patients because most Asian patients with ACS are non-obese.^15,19 The relationship between OSA and the formation of vulnerable plaques can be postulated as follows. Endothelial dysfunction plays an essential role in the process of plaque formation.²⁰ Functional and structural impairments of the endothelium have been reported in OSA patients. Endothelium-dependent vasodilation and nitric oxide production in the endothelium were significantly reduced in untreated OSA patients.²¹ In addition, the number of apoptotic endothelial cells was increased in OSA patients and was positively correlated with AHI.²² The capacity for endothelial repair was also impaired because reduced numbers of circulating endothelial progenitor cells were reported in OSA patients.²³ Chronic intermittent hypoxia, increased oxidative stress with reduced antioxidant capacity, and vascular inflammation, all of which were identified in OSA patients, might also contribute to endothelial dysfunction.^23–25

Plaque rupture or erosion with subsequent rapid thrombus formation is the primary mechanism of ACS.^26,27 Imbalanced collagen production and degradation within plaques also contributes to the thinning of the fibrous cap.²⁸ T cell-derived CD40 stimulates macrophages, which results in the production of matrix-metalloproteinase family members that degrade collagen.²⁹ Because elevated levels of soluble CD40 ligand and MMP-9 activity were found in OSA patients, it is possible that increased collagen degradation, rather than decreased collagen production, is related to the formation of vulnerable plaques.^30,31 Increased sympathetic nerve activity, platelet activity, and blood viscosity, all of which were observed in OSA, might also trigger plaque rupture and thrombosis.^11,12,32

Previous studies reported the increased incidence of cardiac death, cerebrovascular events and TVR in OSA patients with coronary artery disease.^6,14,15 However, the association between OSA and ACS recurrence remained unclear. Our study found that moderate-to-severe OSA was positively correlated with ACS recurrence and MACE during a median follow-up duration of four years. The divergence of ACS- and MACE-free survival estimates increased with increasing follow-up duration. Our findings seem to be consistent with those of Garcia-Rio et al.¹⁸ They assessed 192 patients with acute MI and reported that untreated OSA, defined as AHI of ≥5 events/h, had a higher risk of recurrent MI than non-OSA and treated OSA patients. An additional important finding was that OSA was an independent risk factor of PCI for progressive lesions, although TVR was not different between the two groups. Coronary atherosclerosis might also be accelerated in OSA patients.

CPAP is an established treatment for OSA because it can decrease apnea–hypopnea significantly and inhibits the unfavorable effects of OSA such as increased oxidative stress, elevated sympathetic nerve activity, inflammation and myocardial ischemia.^25,33–35 Two studies reported that CPAP treatment decreased the incidence of cardiac death in OSA patients undergoing PCI⁶ and decreased the incidence of recurrent MI in patients with acute MI.¹⁸ We examined the effects of CPAP treatment in patients with AHI of ≥20 events/h. Although a trend toward a decreased incidence of ACS recurrence and MACEs was observed in patients treated with CPAP, this difference did not reach statistical significance. There are several possible explanations for these inconsistent observations. First, the definition of treated patients was different between our study and previous reports. Patients who declined CPAP treatment or initially complied with treatment but showed poor adherence were defined as untreated patients in both previous studies. In contrast, all patients who initially complied with CPAP treatment were defined as treated patients in the present study. Intolerance to CPAP is a major problem for the use of this treatment.³⁶ Although the beneficial effects of CPAP could not be expected in patients with poor adherence to treatment, it seems appropriate that patients with an initial acceptance but poor adherence were defined as treated patients to accurately predict the effects of CPAP treatment in clinical practice. Second, the lowest AHI level used to indicate CPAP treatment varied among studies: AHI of 5 events/h in the Garcia-Rio et al. study,¹⁸ 15 events/h in the Cassar et al. study⁶ and 20 events/h in the present study. Heterogeneous disease severity in treated patients might also modulate the effectiveness of CPAP treatment. Third, the lack of adequate statistical power due to small sample size (n = 99) might inhibit conclusions from being drawn regarding the effectiveness of CPAP treatment. When we performed a multiple Cox regression analysis for eight risk factors and CPAP treatment in all patients, CPAP treatment was negatively correlated with ACS recurrence, with marginal statistical significance (hazard ratio of CPAP: 0.37, 95% CI 0.13−1.04, p = 0.059).

Limitations of the study

The present study has several possible limitations. First, the follow-up method mainly involved telephone interviews or directly mailing the patients’ attending physicians to confirm the life or death of patients who did not visit our hospital at the scheduled follow-up date. This might be a bias for the accurate estimation of cardiac events. However, all patients who experienced MACE were admitted to our hospital because it is the tertiary referral care center for cardiac emergency in Nagasaki city. Therefore, the incidence of ACS recurrence and MACEs were likely to be accurate. Second, the scheduling of follow-up coronary arteriography was left to the discretion of the attending cardiologist at initial admission. There is a tendency for follow-up coronary arteriography not to be recommended for patients aged ≥85 years or for those with disabling comorbidities. Therefore, the progression of coronary atherosclerosis might be overlooked in these patients and those with silent myocardial ischemia.

Conclusions

The present study found a close relationship between moderate-to-severe OSA and long-term cardiovascular events. Moderate-to-severe OSA increased the incidence of ACS recurrence, MACE and newly necessitated PCI for myocardial ischemia-related progressive lesions. It is highly possible that moderate-to-severe OSA facilitates plaque vulnerability and the progression of coronary atherosclerosis. Polysomnography is essential for patients with ACS because early diagnosis and treatment of OSA might result in a better long-term prognosis.

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References