Day–night pattern of acute ST-segment elevation myocardial infarction onset in patients with obstructive sleep apnea

Abstract

Study Objectives:

Obstructive sleep apnea (OSA) is associated with acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of coronary events, especially during the nighttime. This study sought to investigate the day–night pattern of acute ST-segment elevation myocardial infarction (STEMI) onset in patients with OSA and its impact on cardiovascular adverse events.

Methods:

We prospectively enrolled 397 patients with STEMI, for which the time of onset of chest pain was clearly identified. All participants were categorized into non-OSA (n = 280) and OSA (n = 117) groups. The association between STEMI onset time and major adverse cardiovascular and cerebrovascular events was estimated by Cox proportional hazards regression.

Results:

STEMI onset occurred from midnight to 5:59 am in 33% of patients with OSA, as compared with 15% in non-OSA patients (P < .01). For individuals with OSA, the relative risk of STEMI from midnight to 5:59 am was 2.717 [95% confidence interval (CI) 1.616 − 4.568] compared with non-OSA patients. After a median of 2.89 ± 0.78 years follow-up, symptom onset time was found to be significantly associated with risk of major adverse cardiovascular and cerebrovascular events in patients with OSA, while there was no significant association observed in non-OSA patients. Compared with STEMI presenting during noon to 5:59 pm, the hazard ratios for major adverse cardiovascular and cerebrovascular events in patients with OSA were 4.683 (95% CI 2.024 − 21.409, P = .027) for midnight to 5:59 am and 6.964 (95% CI 1.379 − 35.169, P = .019) for 6 pm to midnight, whereas the hazard ratios for non-OSA patients were 1.053 (95% CI 0.394 − 2.813, P = .917) for midnight to 5:59 am and 0.745 (95% CI 0.278 − 1.995, P = .558) for 6 pm to midnight.

Conclusions:

Patients with OSA exhibited a peak incidence of STEMI between midnight and 5:59 am, which showed an independent association with cardiovascular adverse events.

Citation:

Wang Y, Buayiximu K, Zhu T, et al. Day–night pattern of acute ST-segment elevation myocardial infarction onset in patients with obstructive sleep apnea. J Clin Sleep Med. 2024;20(5):765–775.

BRIEF SUMMARY

Current Knowledge/Study Rationale: This study sought to investigate the day–night pattern of acute ST-segment elevation myocardial infarction onset in patients with obstructive sleep apnea and its impact on cardiovascular adverse events.

Study Impact: Patients with obstructive sleep apnea exhibited a peak incidence of ST-segment elevation myocardial infarction between midnight and 5:59 AM, which showed an independent association with cardiovascular adverse events.

INTRODUCTION

Obstructive sleep apnea (OSA) is a common sleep disorder and is associated with an increased risk of cardiovascular disease. There are 936 million adults who have mild to severe OSA globally, and the number of affected individuals is the largest in China.¹ OSA prevalence is as high as 36%–63% in patients with acute coronary syndrome across various ethnicities.² People with OSA have severe perturbations of autonomic, hemodynamic, humoral, and vascular regulation during sleep that contrast with the physiology of normal sleep.³

In the general population, acute myocardial infarction (AMI) and sudden cardiac death have a day−night pattern of occurrence with a peak in the morning hours (ie, from 6 am to noon) than during the other 6-hour intervals of the day.⁴ Also, there is a marked nadir in the risk of AMI and sudden cardiac death during sleep (ie, from midnight to 5:59 am);⁴ the reason may in part be due to changes in sympathetic activity, baroreflex sensitivity, coagulability, and electrophysiological abnormalities during the waking morning hours. However, OSA is characterized by acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of AMI during the night. Furthermore, the impact of day−night symptom-onset patterns of AMI on prognosis has been previously reported in the general population,^5,6 but little is known about the impact of time dependence of symptom onset on cardiovascular adverse events in patients with OSA. In this study, we tested the hypothesis that people with OSA are more likely to have ST-segment elevation myocardial infarction (STEMI) during midnight to 5:59 am than the other 6-hour intervals of the day. We also tested the hypothesis that the frequency of STEMI from midnight to 5:59 am is higher in people with OSA than in people with non-OSA. Additionally, we assess the impact of day−night symptom-onset patterns of STEMI on cardiovascular adverse events in patients with OSA.

METHODS

Study population

The Prospective Multicenter Cohort Study of Acute ST-segment Elevation Myocardial Infarction project is a large-scale, prospective cohort study aimed at standardizing the management of STEMI patients and improving their prognosis. The study recruited patients from Ruijin hospital, Shanghai Jiao Tong University School of Medicine, and six other general hospitals across Shanghai, China, between September 2018 and September 2023, with follow-up continuing until September 2024. This study is registered at ClinicalTrials.gov (Identifier: NCT05450757).

From March 2019 to March 2022, a total of 638 patients who were diagnosed with STEMI were included in the project at Ruijin hospital, Shanghai Jiao Tong University School of Medicine. Each patient received standard care during index STEMI hospitalization according to current guidelines.^7,8 As a subdivision of the Prospective Multicenter Cohort Study of Acute ST-segment Elevation Myocardial Infarction project, we performed a preliminary survey using the Berlin questionnaire (BQ) and the Epworth Sleepiness Scale for these 638 patients with STEMI. All questionnaire was administered via face-to-face interviews.

The BQ was developed in 1999 and is widely used for detecting OSA. This questionnaire contains 10 questions on the following three categories: snoring behavior (category 1, items 1–5); daytime sleepiness or fatigue (category 2, items 6–9); and presence of obesity or hypertension (category 3, item 10). Patients with persistent and frequent symptoms (> 3–4 times per week) in at least two of the three categories were classified as being at a high risk of developing sleep apnea.⁹ The detailed methods for the BQ were available in the supplemental material (Methods). Among these, we excluded 161 patients who were classified as low risk and 38 patients with high risk who declined to undergo an overnight sleep study. The remaining 439 patients with a high risk for sleep apnea performed an overnight sleep study.

Additionally, among the 439 patients at high risk of OSA, we excluded those with cardiogenic shock and cardiac arrest because they had difficulty reaching clinical stabilization and completing a sleep study during hospitalization. Also excluded were those with a failed sleep study (patients without a minimum of 3 hours of adequate and satisfactory signal recording). The time of onset of STEMI was determined by each patient’s report of the chest pain that prompted hospital admission. Patients without typical chest pain or with uncertain time of onset of STEMI, as well as those receiving regular continuous positive airway pressure therapy and lost to follow-up after discharge, were excluded from the analysis. Three hundred ninety-seven consecutive patients admitted because of STEMI to the critical cardiac care unit and who underwent a sleep study eventually enrolled this study (Figure 1). Written informed consent was obtained from all patients.

Figure 1. Flowchart illustrating the inclusion/exclusion process for the study population.

CPAP = continuous positive airway pressure, OSA = obstructive sleep apnea, STEMI = ST-segment elevation myocardial infarction.

This study was conducted in accordance with the amended Declaration of Helsinki¹⁰ and was approved by the Institutional Research Ethics Committee of Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine (2018-183).

Data collection

Information on the covariables was collected from the electronic medical records. The study variables were demographics (age, sex, body mass index, and smoking), medical history (hypertension, diabetes, atrial fibrillation, and renal failure), clinical variables (peak level of cardiac troponin I, serum or plasma levels of glucose and lipids, liver and renal function), echocardiography, and medications on discharge [dual antiplatelet therapy status, statins, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers). All patients underwent regular laboratory tests within 24 hours and echocardiography within 3 days after admission. Blood samples were drawn from participants after an overnight fast. The detailed methods for echocardiography were available in the supplemental material (Methods). The baseline estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.¹¹ The definitions of these study variables are shown in the Table S1 ^{(523KB, pdf)} in the supplemental material.

Overnight sleep study

Every patient underwent an overnight sleep study using sleep monitors (Philips-Alice NightOne; Phillips, Andover, MA, USA) after clinical stabilization within 7 days after STEMI during hospitalization. Devices were applied to the patients by trained research staff independently at bedtime and were collected the next morning (from 1:00 am to 7:00 am the next day). Patients refrained from caffeine, sedative, or hypnotic drug intake 1 day before their sleep study. Data obtained from monitoring were subjected to automatic computer analysis followed by manual correction by one investigator with no knowledge of the clinical characteristics of the patients.

The following signals were recorded: nasal airflow, thoraco-abdominal movements, snoring episodes, heart rate, and pulse oximetry. Apnea was defined as an absence of airflow for ≥ 10 seconds (obstructive if thoracoabdominal movement was present and central if thoracoabdominal movement was absent). Hypopnea was defined as an airflow reduction of 30% for ≥ 10 seconds with a decrease in arterial oxygen saturation > 4%. The apnea-hypopnea index (AHI; number of apnea or hypopnea events per hour during sleep) was measured as the main parameter. OSA was defined as AHI ≥ 15 events/h. Patients with AHI < 15 events/h were considered as the non-OSA group.^12–14 Patients with AHI ≥ 15 events/h, particularly those with excessive daytime sleepiness, were referred to a respiratory laboratory for further evaluation.

Study endpoints

All patients were followed up for a minimum of 6 months and scheduled at 1 month, 3 months, 6 months, 12 months, and every 6 months thereafter (if applicable). Clinical events were collected via clinic visit, medical records, or telephone calls by research staff who were blinded to the patients’ sleep results. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), which were defined as composite events of all-cause mortality, nonfatal reinfarction, stroke, ischemia-driven revascularization, or hospitalization for unstable angina or heart failure during follow-up. The detailed definitions of endpoints and their components are available in the supplemental material (Methods). All events were independently evaluated by adjudicators blinded to the results of the sleep study. The adjudicators also reviewed the source documents and established the necessity for hospital admission and/or revascularization.

Statistical analysis

The variable distribution was verified using Shapiro−Wilk tests. Continuous variables with normal and skewed distributions were described as the mean ± standard deviation and the medians with interquartile ranges, respectively, whereas categorical variables were described as frequencies and percentages. Missing data for baseline covariates were dealt with using multiple imputation. Differences in continuous data were compared using the Student’s t test or the Mann−Whitney U test, and categorical variables were compared using Chi-square test or Fisher’s exact test when appropriate.

As shiftwork-outcome studies depend on collected data and cannot be randomized, a propensity score-matched analysis was further used to match the baseline characteristics of the two groups and to confirm the results from the multivariable regression analysis in the complete unmatched participants. Propensity-score matched analysis is a widely used statistical technique to reduce the selection bias and adjust for differences in baseline characteristics in studies incapable of randomization.^15,16 The propensity score was computed according to a multivariable logistic model, which included variables that may affect the time of onset of STEMI, including age, sex, body mass index, hypertension, diabetes, smoking history, and multivessel disease. After estimation of the propensity score, the nearest neighbor algorithm was performed to select an equal number of patients in the two groups.^15,17

The proportion of people with OSA who had STEMI during each time interval was compared with the use of the binomial distribution, with the proportion that was expected by chance to have AMI during each quarter of the day (ie, 25%). For patients with OSA, we calculated the relative risk and 95% confidence intervals (CIs) of STEMI during each 6-hour interval as compared with the non-OSA patients. We also performed similar analyses of STEMI in patients with and non-OSA patients for three 8-hour intervals of the day (6 am to 1:59 pm, 2 pm to 9:59 pm, and 10 pm to 5:59 am). These intervals better represent usual sleep−wake cycles. Additionally, logistic regression was used to examine the relationship between OSA and time distribution of STEMI onset. Multivariable logistic regression was employed to control for potential confounding factors such as age, sex, body mass index, smoking history, diabetes mellitus, hypertension, fasting plasma glucose, low-density lipoprotein cholesterol, and estimated glomerular filtration rate.

In patients with OSA, we used the Cox proportional hazards models with the patients who occurred STEMI between noon to 5:59 pm as the reference to calculate adjusted hazard ratios (HRs) and corresponding 95% CIs for the occurrence of MACCEs. We developed three different models by using variables known to influence the risk of MACCEs in patients with STEMI. Model 1 was adjusted for age groups, sex, and body mass index; Model 2 was further adjusted for history of diabetes mellitus, hypertension, systolic blood pressures, diastolic blood pressures, and smoking history; Model 3 was further adjusted for multivessel disease, cardiac troponin I, left ventricular ejection fraction, low-density lipoprotein cholesterol, and estimated glomerular filtration rate. Survivor functions were estimated for each group using the Kaplan−Meier method and were statistically evaluated using a log-rank test of trend.

The statistical significance of predictors is defined as P < .05. Data analyses were performed using SAS software (SAS Institute, Inc., Cary, NC, USA; version 9.4) and Stata (version 15.1, StataCorp, College Station, TX, USA).

RESULTS

Baseline and procedural characteristics of patients with STEMI

In total, 439 consecutive eligible patients with STEMI were prospectively enrolled, of whom 416 underwent a successful overnight sleep study. After exclusion of patients according to predefined criteria, 397 patients were included in the final analysis (Figure 1). Compared with non-OSA patients, patients with OSA were significantly younger (60.00 ± 11.93 vs 65.77 ± 12.42 years; P < .01), mostly male (87.18% vs 77.14%, P = .02), and had higher body mass index (25.73 ± 3.52 vs 24.16 ± 3.18 kg/m²; P < .01). Moreover, patients with OSA were more likely to be smokers (64.96% vs 48.21%; P < .01) and tended to have a higher rate of statins usage (100% vs 96.43%; P = .04). The OSA group has significantly higher estimated glomerular filtration rate (86.80 [interquartile range: 72.90 − 98.10] vs 80.75 [interquartile range: 61.15 − 93.20] 60 ml/(min × 1.73 m²)), left ventricular end-diastolic dimension (50.62 ± 4.66 vs 49.46 ± 5.01 mm; P = .03), and left ventricular end-diastolic volume (124.29 ± 26.58 vs 117.62 ± 28.07 ml; P = .03). No significant differences in other clinical or angiographic characteristics were observed between the two groups (Table 1).

Table 1.

Baseline characteristics grouped by OSA (AHI ≥ 15).

Variables	Entire Unmatched Patients (Before PSM)			Matched Patients (After PSM)
	Non-OSA (n = 280)	OSA (n = 117)	P	Non-OSA (n = 103)	OSA (n = 103)	P
Demographics
Male sex, n (%)	216 (77.14)	102 (87.18)	.02	90 (87.38)	88 (85.44)	.68
Age, years	65.77 ± 12.42	60.00 ± 11.93	<.01	61.47 ± 11.48	61.48 ± 11.29	.99
Body mass index, kg/m2	24.16 ± 3.18	25.73 ± 3.52	<.01	25.15 ± 3.02	25.28 ± 3.25	.76
HR, bpm	83.94 ± 15.73	82.33 ± 13.72	.34	85.55 ± 17.10	81.54 ± 13.66	.06
SBP, mmHg	124.32 ± 20.89	127.67 ± 19.15	.14	126.67 ± 22.35	126.21 ± 17.16	.87
DBP, mmHg	76.05 ± 12.62	80.89 ± 13.85	<.01	79.68 ± 13.97	78.33 ± 11.55	.45
Smoking, n (%)	135 (48.21)	76 (64.96)	<.01	65 (63.11)	66 (64.08)	.88
Medical history
Hypertension, n (%)	175 (62.50)	70 (59.83)	.62	61 (59.22)	60 (58.25)	.89
Diabetes mellitus, n (%)	83 (29.64)	30 (25.64)	.42	26 (25.24)	27 (26.21)	.87
Chronic kidney disease, n (%)	18 (6.43)	6 (5.13)	.63	8 (7.77)	5 (4.90)	.40
Atrial fibrillation, n (%)	3 (1.07)	2 (1.71)	.60	2 (1.94)	2 (1.94)	.99
Baseline tests
FPG, mmol/L	6.93 ± 2.87	6.90 ± 2.74	.93	6.56 ± 2.26	6.87 ± 2.63	.38
HbA1c, %	6.41 ± 1.44	6.31 ± 1.39	.50	6.46 ± 1.40	6.27 ± 1.31	.33
Total cholesterol, mmol/L	4.63 ± 1.23	4.86 ± 1.27	.10	4.66 ± 1.22	4.82 ± 1.25	.35
LDL-C, mmol/L	2.95 ± 1.05	3.14 ± 1.08	.11	3.03 ± 1.08	3.15 ± 1.09	.43
Triglycerides, mmol/L	1.35 (0.99, 1.89)	1.51 (1.17, 2.12)	.40	1.41 (1.03, 1.99)	1.44 (1.15, 2.10)	.89
Creatinine, µmol/L	82.00 (71.00, 103.00)	84.00 (72.00, 96.00)	.21	81.00 (69.00, 96.00)	83.00 (71.00, 96.00)	.16
eGFR, 60 ml/(min × 1.73 m2)	80.75 (61.15, 93.20)	86.80 (72.90, 98.10)	<.01	88.00 (65.40, 99.00)	86.80 (72.90, 98.10)	.18
Peak cTNI, ng/L	38.57 (12.96, 127.95)	45.15 (6.68, 321.95)	.20	35.69 (15.14, 112.00)	45.15 (8.18, 365.89)	.34
Baseline UCG
LA, mm	38.01 ± 3.72	38.64 ± 4.11	.14	38.07 ± 3.45	38.39 ± 4.04	.54
LVEDD, mm	49.46 ± 5.01	50.62 ± 4.66	.03	50.30 ± 4.66	50.44 ± 4.58	.84
LVESD, mm	34.37 ± 5.45	34.74 ± 4.87	.54	35.13 ± 5.43	34.48 ± 4.72	.36
LVPWT, mm	9.46 ± 1.01	9.37 ± 1.02	.57	9.74 ± 0.93	9.33 ± 1.01	.04
LVEDV, ml	117.62 ± 28.07	124.29 ± 26.58	.03	121.92 ± 27.46	123.17 ± 26.10	.74
LVESV, ml	51.23 ± 20.72	52.50 ± 18.00	.57	54.08 ± 21.73	51.49 ± 17.32	.35
LVEF, %	56.70 ± 8.58	57.92 ± 6.94	.14	56.07 ± 8.03	58.25 ± 6.95	.05
LVMI, g/m2	113.49 ± 26.69	110.77 ± 24.64	.55	117.12 ± 28.92	112.12 ± 24.82	.37
Number of diseased coronary vessels			.54			.53
Single vessel, n (%)	64 (22.86)	30 (25.64)		24 (23.30)	27 (26.73)
Multiple vessels, n (%)	216 (77.14)	87 (74.36)		78 (75.73)	74 (73.27)
Treatment			.46			.79
Conservative medication, n (%)	14 (5.00)	5 (4.31)		7 (6.80)	5 (4.90)
PTCA, n (%)	8 (2.86)	4 (3.45)		5 (4.85)	4 (3.92)
PCI, n (%)	258 (92.14)	106 (91.38)		91 (88.35)	93 (91.18)
Medications on discharge
DAPT, n (%)	280 (100.00)	117 (100.00)	1.00	103 (100.00)	103 (100.00)	1.00
β-blockers, n (%)	248 (88.57)	107 (91.45)	.39	95 (92.23)	94 (91.26)	.80
ACEIs/ARBs, n (%)	203 (72.50)	95 (81.20)	.07	84 (81.55)	83 (80.58)	.86
Statins, n (%)	270 (96.43)	117 (100.00)	.04	101 (98.06)	103 (100.00)	.16
Sleep study
AHI, events/h	8.79 ± 4.03	33.57 ± 13.76	<.01	8.96 ± 2.99	32.29 ± 12.98	<.01
ODI, events/h	8.20 (7.60, 19.60)	20.85 (10.05, 37.90)	<.01	8.80 (5.20, 17.90)	19.30 (9.90, 36.10)	<.01
Minimum SaO2, %	90.23 ± 5.18	80.34 ± 9.00	<.01	87.75 ± 4.77	80.66 ± 8.97	<.01
Mean SaO2, %	95.81 ± 1.33	94.31 ± 1.60	.04	95.75 ± 0.97	94.34 ± 1.64	.04
Time with SaO2 < 90%, %	0.2 (0.0, 1.1)	5.1 (1.2, 12.9)	<.01	0.2 (0.1, 1.1)	4.9 (1.3, 10.7)	<.01

Data are presented as mean ± standard deviation, median (first quartile, third quartile), or n (%). ACEI = angiotensin-converting enzymes inhibitor, AHI = apnea-hypopnea index, ARB = angiotensin receptor blocker, cTnI = cardiac troponin I, DAPT = dual antiplatelet therapy, DBP = diastolic blood pressure, eGFR = estimated glomerular filtration rate, FPG = fasting plasma glucose, HR = heart rate, LA = left atrium diameter, LDL-C = low-density lipoprotein cholesterol, LVEDD = left ventricular end-diastolic dimension, LVEDV = left ventricular end-diastolic volume, LVEF = left ventricular ejection fraction, LVESD = left ventricular end-systolic dimension, LVESV = left ventricular end-systolic volume, LVMI = left ventricular mass index, LVPWT = left ventricular posterior wall thickness, ODI = oxygen desaturation index, OSA = obstructive sleep apnea, PCI = percutaneous coronary intervention, PSM = propensity score matching, PTCA = percutaneous transluminal coronary angioplasty, SaO₂ = arterial oxygen saturation, SBP = systolic blood pressure, UCG = echocardiography.

AHI ranged from 0.7 to 69.3 events/h. Oxygen desaturation index was significantly greater in patients with OSA than in those without OSA [8.20 (7.60, 19.60) vs 20.85 (10.05, 37.90), P < .01]. Patients with OSA exhibited lower minimum oxygen saturation than those non-OSA (890.23 ± 5.18 vs 80.34 ± 9.00, P < .01). Detailed information is described in Table 1.

In order to explore the time intervals of onset of STEMI in patients with OSA, we also performed a propensity score matching analysis. Patients were matched using a nearest neighbor algorithm, and the procedure yielded two well-matched subgroups of 103 patients, thus successfully matching 88.03% of the OSA group. In the matched participants, clinical and angiographical risk profiles were well balanced between the two matched groups (Table 1).

Time distribution of STEMI onset during 6-hour intervals

The time intervals variation of onset of STEMI is presented in Figure 2. There existed an uneven distribution with night peak of onset of STEMI in patients with OSA as compared to non-OSA patients (33% vs 15%, P < .01). The incidence of STEMI onset between 6 am and noon was significantly higher in non-OSA patients than in patients with OSA (40% vs 30%, P = .034). The incidence of STEMI onset between noon and 5:59 pm was significantly lower in patients with OSA than in non-OSA patients (16% vs 27%, P < .01) (Figure 2A). In propensity-score matched analysis patients, the incidence of STEMI onset between midnight and 5:59 am was also significantly higher in patients with OSA than in non-OSA patients (33% vs 19%, P = .047) (Figure 2B).

Figure 2. Day−night pattern and relative risk of AMI during six-hour intervals in the entire patient population and propensity score-matched patients.

(A) Day−night pattern of AMI in 117 patients with and 280 non-OSA patients. (B) Day−night pattern of AMI in propensity score-matched patients. (C) Relative risk of AMI during six-hour intervals for 117 patients with OSA; the reference group consists of 280 entire non-OSA patients. (D) Relative risk of AMI during six-hour intervals in propensity score matched patients; the reference group consists of 115 non-OSA patients. The squares represent the relative risk point estimates and the I bars the 95% confidence intervals. AMI = acute myocardial infarction, OSA = obstructive sleep apnea.

Relative risk of STEMI onset during 6-hour intervals

Compared with the non-OSA patients, patients with OSA experienced higher risk of STEMI onset with 2.717 (95% CI 1.616 − 4.568) at time from midnight to 5:59 am, 0.679 (95% CI 0.424 − 1.088) from 6 am to noon, 1.177 (95% CI 0.673 − 2.059) from 6 pm to midnight, and lower risk of 0.511 (95% CI 0.285 − 0.913) from noon to 5:59 pm (Figure 2C). Similar results were observed in the propensity-score matched analysis groups with a relative risk of STEMI onset of 2.327 (95% CI 1.210 − 4.474) from midnight to 5:59 am in OSA group compared with the non-OSA group, lower risk of 0.509 (95% CI 0.286 − 0.906) from 6 am to noon, 0.599 (95% CI 0.281 − 1.281) from noon to 5:59 pm, and 1.493 (95% CI 0.766 − 2.910) from 6 pm to midnight (Figure 2D).

Sleep–wake cycles

The sleep−wake cycles details are described in the supplemental material (Results and Figure S1 ^{(523KB, pdf)} ). Included are the day–night pattern of STEMI onset (Figure S1A ^{(523KB, pdf)} and Figure S1B ^{(523KB, pdf)} ) and the relative risk of STEMI onset during the three time intervals that represent usual sleep–wake cycles (Figure S1C ^{(523KB, pdf)} and Figure S1D ^{(523KB, pdf)} ). Similar results were evident for the analyses based on three 8-hour time intervals. The results from the matched patients were consistent with the findings from the entire unmatched participants.

Univariate and multivariate logistic regression analysis to discern the association between OSA and time distribution of STEMI onset

During a median follow-up of 2.89 ± 0.78 years, the primary outcome of MACCEs occurred in 112 (28.21%) patients (Table S2 ^{(523KB, pdf)} ). According to 6-hour intervals and sleep−wake cycles, the results of univariate and multivariate logistic regression analysis of the associated between OSA and time distribution of STEMI onset are shown in Table S3 ^{(523KB, pdf)} and Table S4 ^{(523KB, pdf)} . After fully adjusting for confounding factors compared with the non-OSA patients, patients with OSA experienced a higher risk of STEMI onset from midnight to 5:59 am 2.467 (95% CI 1.401 − 4.345, P = .002), whereas OSA was no longer associated with STEMI onset from 6 am to noon, from 6 pm to midnight, and from noon to 5:59 pm The results from the matched patients were consistent with the findings from the entire unmatched participants.

Association of the time of onset of STEMI with MACCEs

Compared with the STEMI onset from noon to 5:59 pm, STEMI onset from midnight to 5:59 am was associated with increased risks of MACCEs for OSA group patients (adjusted HR: 4.683; 95% CI 2.024 − 21.409; P = .027) (Table 2). On the contrary, time of STEMI onset was not associated with follow-up MACCEs for non-OSA group patients (Table 2 and Figure 3). Only in patients with OSA did there exist a weak relationship between the STEMI onset time (midnight to 5:59 am) and MACCEs with borderline significance (P = .045, log-rank test) by comparing with the remaining 18 hours of the day (Figure 3).

Table 2.

Association of day−night pattern of acute myocardial infarction with long-term adverse events in the OSA and non-OSA patient population.

	HR (95% CI) for MACCEs
	Midnight−5:59 am	6 am−11:59 am	Noon−5:59 pm	6 pm−11:59 pm
OSA
Model 1	2.245 (1.392–3.950)	0.625 (0.173–2.256)	1 (reference)	2.287 (1.093–4.213)
P	.041	.473		.048
Model 2	3.816 (1.925–15.751)	2.184 (0.468–10.191)	1 (reference)	5.698 (1.268–25.605)
P	.034	.320		.023
Model 3	4.683 (2.024–21.409)	3.847 (0.701–21.114)	1 (reference)	6.964 (1.379–35.169)
P	.027	.121		.019
Non-OSA
Model 1	0.515 (0.210–1.264)	0.725 (0.356–1.477)	1 (reference)	0.555 (0.240–1.285)
P	.147	.375		.169
Model 2	0.574 (0.228–1.448)	0.711 (0.316–1.600)	1 (reference)	0.719 (0.300–1.724)
P	.240	.410		.460
Model 3	1.053 (0.394–2.813)	1.171 (0.503–2.723)	1 (reference)	0.745 (0.278–1.995)
P	.917	.714		.558

Model 1, adjusted for age, sex, and BMI. Model 2, Model 1 + hypertension, diabetes mellitus, SBP, DBP, and smoking status. Model 3, Model 2 + number of diseased coronary vessels, cTnI, LVEF, LVEDV, LDL-C, usage of statins, and eGFR. BMI = body mass index, CI = confidence interval, cTnI = cardiac troponin I, DBP = diastolic blood pressure, eGFR = estimated glomerular filtration rate, HR = hazard ratio, LDL-C = low-density lipoprotein cholesterol, LVEDV = left ventricular end-diastolic volume, LVEF = left ventricular ejection fraction, MACCE = major adverse cardiovascular and cerebrovascular event, OSA = obstructive sleep apnea, SBP = systolic blood pressure.

Figure 3. The Kaplan−Meier survival curve of onset time of acute myocardial infarction on MACCEs-free survival.

(A) Cumulative incidence of MACCEs in patients with OSA. (B) Cumulative incidence of MACCEs in non-OSA patients. MACCE = major adverse cardiac and cerebrovascular event, OSA, obstructive sleep apnea.

DISCUSSION

This study shows that patients with OSA have a significantly increased risk of STEMI onset during midnight to 5:59 am, which is in striking contrast to the nadir of STEMI during this time in non-OSA patients. In the analysis of STEMI onset from midnight to 5:59 am and from 10 pm to 5:59 am (which is more relevant to sleep-related pathophysiology), a marked nocturnal peak in STEMI onset was observed in patients with OSA. By contrast, the non-OSA patients had a day−night pattern of STEMI onset with a peak from 6 am to noon. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, and other confounding factors, patients with OSA with STEMI onset from midnight to 5:59 am had 4.68 times the risk of MACCEs occurrence at a median follow-up of 2.89 years, while for non-OSA patients no relationship was observed between the onset time of STEMI and the MACCEs occurrence. To the best of our knowledge, this is the first study to investigate the relationship between the time of onset of symptoms of STEMI and subsequent adverse events during a long-time follow-up among patients with OSA.

OSA prevalence is as high as 40%–80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke.^3,18 Despite its high prevalence in patients with coronary artery disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. Actually, the presence of OSA was associated with a significantly higher risk of subsequent cardiovascular events after acute coronary syndrome onset.^19,20 In the Sleep and Stent study (68.5% acute coronary syndrome), patients with OSA had 1.57 times the risk of incurring an MACCE after percutaneous coronary intervention at 1.9 years follow-up.²¹ The latest research has shown that OSA was associated with a greater risk of MACCEs in women who were hospitalized for acute coronary syndrome (28.1% vs 18.8%; adjusted HR 1.68; 95% CI 1.02 − 2.78, P = .042) but not in men (21.6% vs 17.5%; adjusted HR 1.22; 95% CI 0.96 − 1.54, P = .100).¹⁹ Although the association of OSA with subsequent cardiovascular events in AMI patients is well documented, data on the impact of the onset time of STEMI on this association are limited.

In the general population, STEMIs have a time interval pattern of occurrence with a peak in the morning hours (ie, from 6 am to noon) as compared to during the other 6-hour intervals of the day;⁴ the reason may in part be due to changes in sympathetic activity, baroreflex sensitivity, coagulability, and electrophysiological abnormalities during the waking morning hours.²² Nevertheless, people with OSA have severe perturbations of autonomic, hemodynamic, humoral, and vascular regulation during sleep that contrast with the physiology of normal sleep. It is not certain if a similar time interval pattern of STEMI symptom onset occurs in patients with OSA, and its possible impact on clinical outcomes is unknown. Few long-term data are available. Previous study explored the day−night variation of STEMI in patients with OSA, but there were problems such as a small sample size, no follow-up, or no optimal drug treatment.²³ Our findings not only corroborate previous studies, which showed a peak in symptom onset of STEMI during midnight to 5:59 am for patients with OSA,²⁶ but also demonstrated that, despite that most patients had accepted guideline-determined medication therapy, the effects of time intervals rhythm on STEMI occurrence have remained constant.

Mooe et al²⁴ have shown that the severity of hypoxemia is a major determinant of ST depression occurring during sleep, and in patients with OSA, episodes of nocturnal myocardial ischemia are common in patients with angina pectoris.^25,26 Our study found the incidence of STEMI onset, nadir arterial oxygen saturation, and nadir HR was synchronously higher between midnight and 2:59 am than 3 am to 5:59 am; these findings initially indicated that perturbations of autonomic and hypoxia may occur in synchronization with STEMI onset.

Hypoxia, oxidative stress, and systemic inflammation link OSA and cardiovascular and metabolic consequences, including coronary artery disease.^18,27,28 Several acute pathophysiological mechanisms during sleep time in patients with OSA may be responsible for their altered day−night pattern of STEMI. OSA-related autonomic nervous system fluctuations are typified by enhanced parasympathetic activation during respiratory events and sympathetic surges subsequent to respiratory events, which contribute to increased blood pressure.^29,30 In our research, incidence of STEMI onset, nadir arterial oxygen saturation, and nadir HR occurred mostly between midnight and 3 am; this suggests to some extent that the autonomic nervous system fluctuations associated with apnea may be also associated with myocardial ischemia. In addition, there are prominent intrathoracic pressure fluctuations in OSA secondary to attempts to breathe against an obstructed upper airway.³¹ Obstructed breathing with negative intrathoracic pressures increases cardiac wall stress.³² Peripheral vasoconstriction and increased cardiac output (due to changes in cardiac transmural pressures upon termination of apneas) lead to dramatic surges in arterial blood pressure. These hemodynamic stresses in the setting of simultaneous hypoxemia and increased myocardial oxygen demand may promote acute nocturnal cardiac ischemia.^24,26 OSA is also associated with factors that may increase the risk of nocturnal coronary thrombosis, including platelet activation during sleep,^33–35 elevated fibrinogen levels, increased whole blood viscosity, and decreased fibrinolytic activity. This prothrombotic milieu in the vasculature is likely a key contributing factor toward the development of STEMI. These processes may be responsible for the shift in the timing of STEMI onset from the morning hours to the night in patients with OSA. In addition, STEMI patients with night symptom onset might have a higher cardiomyocyte vulnerability to ischemia/reperfusion injury, which is regulated by cardiomyocyte circadian clock genes as has been suggested.³⁶

In the present study, for the first time we demonstrated that STEMI occurring time was a prognostic factor for MACCEs exclusively for patients with OSA, with the worst outcomes occurring in the midnight to 5:59 am group. However, time of STEMI onset was not associated with MACCEs in non-OSA patients. In the general population, sex should be considered in studying the impact of the circadian system on myocardial infarction. Xu et al³⁷ have shown that the worst in-hospital outcomes occurred for male STEMI patients presenting during midnight to 5:59 am but not in women or the total population; in addition, symptom onset time was not associated with MACCEs in both sexes or the total population, which was consistent with our research.

In summary, we have demonstrated that patients with OSA have an altered diurnal variation of AMI, which is consistent with the unique nocturnal pathophysiology of OSA. These findings highlight a potential causative role of OSA in the development of acute coronary syndromes, and positive treatment of patients with OSA may help to reduce nighttime myocardial infarction and mortality. Our data further suggest that those patients who experience the onset of STEMI during the usual sleep hours should be further evaluated if the patient has potential OSA.

There are some limitations to our present study. One limitation relates to the recognized difficulty of establishing the diagnosis and timing of chest pain. The exact time of onset of symptoms is sometimes hard to determine because the information is self-reported. Preinfarction angina may also have occurred and contributed further to an imprecise determination of STEMI onset. Second, this study includes exclusive recruitment of patients who can tolerate the sleep study, which may conceal the real influence of OSA on more severe patients complicated with heart failure, severe kidney diseases, or infection, possibly resulting in an underestimated rate of late adverse events. Third, this study is an interim analysis as a subdivision of an ongoing larger study, and the sample size of our study was relatively small. Large-scale multicenter double-blind prospective clinical studies may be required for further confirmation of the influence of OSA on STEMI patients. Fourth, the overnight sleep study was conducted with a portable diagnostic device instead of supervised in-laboratory polysomnography, which may underestimate the severity of OSA. On the other hand, we use the BQ for preliminary screening of patients with STEMI and excluded those with a low risk of OSA. However, in patients after AMI, the presence of comorbidities can affect the performance of diagnostic tests, potentially leading to false-positive or false-negative tests. In the present study, only 29.5% of the BQ classified high-risk patients finally diagnosed with OSA. As reported, the overall diagnostic accuracy of the BQ for sleep-disordered breathing using the AHI cutoff of 15 events/h was 49%.³⁸ A possible explanation is that these comorbidities may produce changes in symptoms that are similar to OSA symptoms. Although the BQ is a commonly used screening tool to detect the risk for sleep-disordered breathing in the clinical setting, it performed with modest sensitivity, and the specificity was poor. These would have introduced biases to the study.³⁸ Finally, our study did not assess whether the risk of AMI during nighttime is lower in patients with OSA who are on adherent treatment (eg, continuous positive airway pressure, oral appliance, etc.).

CONCLUSIONS

This study shows that the day−night pattern in the onset of STEMI in patients with OSA is strikingly different from non-OSA patients. Patients with OSA have a peak onset of STEMI during midnight to 5:59 am. In addition, for patients with OSA, STEMI onset from midnight to 5:59 am had worse cardiovascular prognosis than those without. Further study needs to discover the underlining mechanisms of the impact of the circadian system on patients with OSA with STEMI.

DISCLOSURE STATEMENT

All authors played a role in writing the manuscript and had full access to the data. The authors report no conflicts of interest.

ABBREVIATIONS

AHI

apnea-hypopnea index

AMI

acute myocardial infarction

BQ

Berlin questionnaire

CI

confidence interval

HR

hazard ratio

MACCE

major adverse cardiovascular and cerebrovascular event

OSA

obstructive sleep apnea

STEMI

ST-segment elevation myocardial infarction