Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Original Article
The Long-Term Prognostic Role of Nighttime Resting Heart Rate in Obstructive Sleep Apnea in Patients with Acute Coronary Syndrome
Qingjie Xin, Hui Ai, Wei Gong, Wen Zheng, Xiao Wang, Yan Yan, Bin Que, Siyi Li, Zekun Zhang, Xiuhuan Chen, Yun Zhou, Jingyao Fan, Shaoping Nie
著者情報
キーワード: Acute coronary syndrome, Obstructive sleep apnea, Heart rate, Prognosis
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2024 年 31 巻 5 号 p. 603-615

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Abstract

Aim: A close relationship exists between resting heart rate (RHR) and obstructive sleep apnea (OSA). Still, the prognostic importance of nighttime RHR in patients with acute coronary syndrome (ACS) with or without OSA remains unclear.

Methods: In this prospective cohort study, OSA was defined as an apnea–hypopnea index of ≥ 15 events/h, and the high nighttime RHR (HNRHR) was defined as a heart rate of ≥ 70 bpm. The primary endpoint was a major adverse cardiovascular and cerebrovascular event (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, or hospitalization for heart failure.

Results: Among the 1875 enrolled patients, the mean patient age was 56.3±10.5 years, 978 (52.2%) had OSA, and 425 (22.7%) were in HNRHR. The proportion of patients with HNRHR is higher in the OSA population than in the non-OSA population (26.5% vs. 18.5%; P＜0.001). During 2.9 (1.5, 3.5) years of follow-up, HNRHR was associated with an increased risk of MACCE in patients with OSA (adjusted HR: 1.56, 95% CI: 1.09–2.23, P=0.014), but not in patients without OSA (adjust HR: 1.13, 95% CI: 0.69–1.84, P=0.63).

Conclusions: In patients with ACS, a nighttime RHR of ≥ 70 bpm was associated with a higher risk of MACCE in those with OSA but not in those without it. This identifies a potential high-risk subgroup where heart rate may interact with the prognosis of OSA. Further research is needed to determine causative relationships and confirm whether heart rate control impacts cardiovascular outcomes in patients with ACS-OSA.

Clinical Trial Registration: Clinicaltrials.gov; No: NCT03362385.

Introduction

Obstructive sleep apnea (OSA) is a complex, inadequately investigated, and prevalent chronic condition characterized by recurring episodes of upper respiratory collapse, affecting over 170 million individuals globally, with a predicted prevalence exceeding 50% in certain countries1). OSA has been shown to initiate and worsen coronary atherosclerosis and is closely linked to poor outcomes in patients with acute coronary syndrome (ACS)2, 3). In our previous report, the presence of OSA predicted adverse cardiovascular events after ACS in different sub-populations4, 5). Resting heart rate (RHR) is a clinical parameter that represents the number of heartbeats per minute in an individual’s tranquil state and serves as a readily available prognostic marker for cardiovascular health6). RHR has also been identified as a predictor of mortality and cardiovascular disease in patients with ACS7), and controlling it in patients with ACS is of great importance. Although a variety of drugs such as β-blockers are now routinely used to control RHR in patients with ACS, some patients still suffer from suboptimal heart rate control8). Alterations in RHR and OSA often coexist and exhibit a strong association with the development of coronary artery disease9, 10). The presence of OSA, which involves recurring episodes of airway obstruction leading to microarousals and hypoxemia, can contribute to autonomic dysfunction11), and it is widely acknowledged that RHR serves as an indicator of sympathetic activity and autonomic equilibrium within the body. Research has shown that patients with OSA typically have a higher RHR12). However, the extent to which the prognostic value of RHR in patients with ACS differs according to OSA status remains uncertain. In this study, we aim to investigate the correlation between RHR and long-term cardiovascular events among patients with ACS with or without OSA.

Methods

Study Design and Population

This is a sub-study of the OSA-ACS project (NCT03362385), a prospective, observational, single-center study that enrolled patients with ACS who were admitted to Beijing Anzhen Hospital, Capital Medical University, from June 2015 to January 2020, wherein portable sleep apnea monitoring was performed on all enrolled patients according to the inclusion criteria, to evaluate the association between OSA and cardiovascular outcomes in patients with ACS. ACS was defined as ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA). Specifically, STEMI was defined as symptoms of myocardial ischemia with persistent ST-segment elevation or new left bundle-branch block on the electrocardiogram (ECG) and the subsequent release of biomarkers of myocardial necrosis. NSTEMI was defined as symptoms of ischemia with positive cardiac biomarkers but without ST-segment elevation. UA was defined as symptoms or accelerating patterns of anginal symptoms with or without ECG changes indicative of ischemia but without elevation in cardiac biomarkers13, 14).

The inclusion criteria included: (1) patients who are 18–85 years old; (2) a discharge diagnosis of ACS, including STEMI, NSTEMI, and UA; (3) signed informed consent. The exclusion criteria included: (1) cardiac arrest or cardiogenic shock;(2) history of malignancy; (3) inability to complete sleep monitoring tests; (4) atrial fibrillation; (5) patients with predominantly central sleep apnea (≥ 50% central events and central apnea–hypopnea index (AHI) of ≥ 10 breaths/hour) and those already undergoing regular continuous positive airway pressure treatment (＞4 hours/day or ＞21 days/month).

This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (2013025). All participants provided written informed consent.

Sleep Study and Management

All enrolled patients used a Type III portable sleep monitoring device (ApneaLink Air, ResMed, Australia) during their stay in the hospital. The devices were applied independently by trained study staff at bedtime, and the results were collected the following morning. The output of the portable diagnostic device was recorded in a dedicated OSA database by a researcher who did not know the patient’s clinical characteristics. Sleep studies were scored according to the criteria indicated by the American Academy of Sleep Medicine15) based on the recorded signals of nasal airflow, chest and abdominal movements, snoring, heart rate, and oxygen saturation (SaO2). Apnea was defined as an airflow of ≤ 10 seconds (OSA was indicated if chest and abdominal movements were present; central sleep apnea if chest and abdominal movements were not present). Hypopnea was defined as a 30% reduction in airflow for ≥ 10 seconds along with a ＞4% decrease in arterial SaO2. AHI was defined as the number of apneas and hypopneas recorded per hour. Based on guidelines and relevant literature9), in this study, we categorized patients into the OSA (AHI ≥ 15 times/h) and non-OSA groups (AHI ＜15 times/h). The hypoxemic burden was quantified by calculating oxygen desaturations per hour of sleep (ODI) and the percentage of time with a SaO2 of ＜90% (T90)11). The Epworth Sleepiness Scale was used in this study to analyze patients’ self-reported degree of daytime sleepiness.

Standardized ACS treatment is performed in all hospitalized patients according to current guidelines16). Percutaneous coronary intervention (PCI) stenting or coronary artery bypass grafting is performed when surgery is required. Patients with OSA, especially those with excessive daytime sleepiness, are referred to a sleep center for further evaluation and treatment.

Measurements of RHR

The nighttime RHR is measured using the Type III portable sleep monitoring device, and the average heart rate during sleep monitoring is taken as the nighttime RHR. A cutoff of 70 bpm was selected in the present study; published evidence has suggested that the risk associated with heart rate rises steeply above this value10, 17). Patients were divided into a high nighttime RHR (HNRHR) group (≥ 70 bpm) and a non-HNRHR group (＜70 bpm).

Endpoints and Follow-Up

All patients were followed up at 1, 3, 6, 9, and 12 months after discharge and every 6 months thereafter via outpatient visits or telephone calls. The follow-up and all clinical events adjudication were conducted by an independent clinical events committee blinded to the patient’s clinical characteristics and sleep apnea monitoring results. The primary endpoint was a major adverse cardiac and cerebrovascular event (MACCE), which was the composite endpoint of cardiogenic death, non-fatal myocardial infarction, non-fatal stroke, ischemia-driven revascularization, and hospitalization for heart failure. Secondary endpoints include individual events of MACCE. All endpoints were defined according to the proposed definitions by the Standardized Data Collection for Cardiovascular Trials Initiative18) and have been previously described5, 19). For patients experiencing multiple events, the counting was based on the first occurrence from the baseline.

Statistical Analysis

Quantitative data are shown as mean±standard deviation (SD) or median (first and third quartiles) and assessed using Student’s t-test or Mann–Whitney U test. Qualitative data were presented as percentages (%) and assessed using X2 statistics or the Fisher exact test. Kaplan–Meier curves were generated for the non-HNRHR and HNRHR groups stratified by OSA categories. The Cox proportional hazard model was performed to determine whether heart rate was an independent predictor of the events, stratified by OSA categories. Confounding factors with potential clinically relevant endpoints or that showed a univariate relationship with endpoints were adjusted in multivariable models. Model 1 was unadjusted. Model 2 included age, sex, and body mass index (BMI). Model 3 included variables in model 2 plus a current smoking status, history of hypertension, diabetes, dyslipidemia, prior myocardial infarction, prior stroke, clinical presentation (STEMI vs. NSTE-ACS), left ventricular ejection fraction (LVEF), history of beta-blocker administration, and AHI. The Cox proportional hazards assumption was checked using log(−log[survival]) − log(time) plots or the Schoenfeld residuals test as appropriate. The results of Cox proportional hazard model are shown as hazard ratio (HR) and 95% confidence intervvals (CI). Multiplicative interaction terms were included in the fully adjusted models to evaluate if heart rate modified the associations between OSA and the risk of cardiovascular events. All analyses were conducted using SPSS 25.0 (IBM SPSS). Two-sided P＜0.05 defined statistical significance.

Results

Baseline Clinical Characteristics

A total of 1875 patients with ACS were enrolled, and 425 (22.7%) of these were included in the HNRHR group. Compared with patients in the non-HNRHR group, patients in the HNRHR group were younger, had a higher BMI, lower LVEF, higher prevalence of diabetes, STEMI, prior stroke, and higher levels of sleep study indicators (Supplementary Table 1). The proportion of patients in the HNRHR group is higher in the OSA population than in the non-OSA population. (26.5% vs. 18.5%; P＜0.001). The study flow chart is shown in Fig.1.

Supplementary Table 1.Demographic and clinical characteristics in high night-time resting heart (HNRHR) versus non- HNRHR groups

Variables Non-HNRHR (n= 1450) HNRHR (n= 425) P-value
Demographics
Age, years 56.6±10.3 55.2±11.1 0.019
Male 1218 (84.0) 367 (86.4) 0.238
BMI, kg/m2 26.9±3.6 27.6±3.8 ＜0.001
Neck, circumference, cm 40.5 (38.0, 43.0) 41.0 (39.0, 44.0) = 0.001
Waist-to-hip ratio 0.98 (0.94, 1.01) 0.99 (0.96, 1.02) ＜0.001
Systolic BP, mmHg 126.5 (117, 138) 126 (116, 139) 0.669
diastolic BP, mmHg 76 (70, 84) 76 (70, 86) 0.149
Medical history
Hypertension 942 (65.0) 263 (61.9) 0.243
Diabetes 438 (30.2) 157 (36.9) 0.009
Hyperlipidaemia 487 (33.6) 139 (32.7) 0.735
Prior myocardial 239 (16.5) 68 (16.0) 0.813
Prior stroke 136 (9.4) 59 (13.9) 0.007
Prior PCI 306 (21.1) 84 (19.8) 0.550
Prior CABG 19 (1.3) 9 (2.1) 0.228
Current smoking 497 (34.3) 136 (32) 0.324
Baseline laboratory test
LVEF, % 62 (58, 66) 60 (53, 64) ＜0.001
Total cholesterol, mmol/L 4.22±1.1 4.43±1.12 0.001
Triglyceride, mmol/L 1.86±1.62 2.07±2 0.029
HDL-C, mmol/L 1.03±0.24 1.02±0.23 0.575
LDL-C, mmol/L 2.54±0.91 2.69±0.93 0.002
Creatinine, mmol/L 75.6±18.13 76.02±20.02 0.683
Hemoglobin A1C, mmol/L 6.49±1.37 6.69±1.45 0.019
hs-CRP, mg/L 4.87±7.51 8.09±9.22 ＜0.001
History of medications use
β-blockers 364 (26.1) 103 (25.4) 0.079
CCBs 364 (26.0) 81 (20.1) 0.018
Medications on discharge
Aspirin 1412 (97.4) 417 (98.1) 0.387
P2Y12 inhibitors 1326 (91.4) 394 (92.7) 0.408
β-blockers 1081 (74.6) 369 (86.8) ＜0.001
ACEIs/ARBs 886 (61.1) 275 (64.7) 0.179
Statins 1429 (98.6) 418 (98.4) 0.766
CCBs 317 (21.9) 78 (18.4) 0.119

The data is presented as mean±SD, median (first quartile to third quartile), or n (%). Abbreviations: ACEI, angiotensin-converting enzymes inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; CABG, coronary artery bypass grafting; CCBs, Calcium channel blockers; Hs-CRP, High sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCI, percutaneous coronary intervention;

Fig.1.

Study flowchart

The baseline characteristics of the HNRHR and non-HNRHR groups categorized by OSA are shown in Table 1. Regardless of OSA, patients with HNRHR exhibited higher waist-to-hip ratios, C-reactive protein levels, and total cholesterol levels; lower LVEF; and were more likely to be diagnosed with STEMI, undergo PCI procedures, and receive β-blockers medications on discharge. In the non-OSA group, patients with HNRHR were more likely to have a prior stroke and had a higher level of low-density lipoprotein cholesterol. In the OSA group, patients with HNRHR were younger, had a higher BMI, and were more likely to have diabetes. In both the OSA and non-OSA groups, other characteristics were generally well-matched between non-HNRHR and HNRHR patients.

Table 1.Demographic and clinical characteristics by high night-time resting heart rate (HNRHR) and obstructive sleep apnea (OSA) categories

Variables

ALL

(N= 1875)

 Non-OSA OSA

non-HNRHR

(n= 731)

HNRHR

(n= 166)

 p-value

non-HNRHR

(n= 719)

HNRHR

(n= 259)

 p-value
Demographics
Age, years 56.3±10.5 56.3±10.2 55.7±11.2 0.513 57.0±10.3 54.9±11.1 0.007
Male 1616 (84.6) 591 (80.8) 141 (84.9) 0.131 627 (87.2) 226 (87.9) 0.982
BMI, kg/m2 27.1±3.6 25.9±3.4 26.3±3.4 0.269 27.9±3.46 28.5±3.8 0.016
Neck, circumference, cm 41 (38-43) 40 (37-42) 40 (38-42) 0.135 41 (39-44) 42 (39-44) 0.027
Waist-to-hip ratio 0.98 (0.95-1.02) 0.97 (0.93-1.00) 0.98 (0.94-1.01) 0.018 0.99 (0.96-1.02) 1.00 (0.96-1.03) 0.040
Systolic BP, mmHg 126 (117-138) 126 (117-138) 125 (114-136) 0.286 127 (117-138) 127 (117-139) 0.832
diastolic BP, mmHg 76 (70-85) 75 (69-83) 75 (69-81) 0.880 77 (70-85) 78 (70-87) 0.130
Medical history
Hypertension 1205 (64.3) 450 (61.6) 95 (57.2) 0.302 492 (68.4) 168 (64.9) 0.294
Diabetes 595 (31.7) 226 (30.9) 60 (36.1) 0.192 212 (29.5) 97 (37.5) 0.018
Hyperlipidaemia 626 (33.4) 243 (33.2) 49 (29.5) 0.355 244 (33.9) 90 (34.7) 0.813
Prior myocardial 307 (16.4) 111 (15.2) 26 (15.7) 0.877 128 (17.8) 42 (16.2) 0.564
Prior stroke 195 (10.4) 58 (7.9) 26 (15.7) 0.002 78 (10.8) 33 (12.7) 0.410
Prior PCI 390 (20.8) 130 (17.8) 31 (18.7) 0.787 176 (24.5) 53 (20.5) 0.191
Prior CABG 28 (1.5) 9 (1.2) 2 (1.2) 0.978 10 (1.4) 7 (2.7) 0.166
Smoking 0.439 0.732
No 633 (33.8) 261 (35.7) 54 (32.5) 236 (32.8) 82 (31.7)
Yes 1242 (66.2) 470 (64.3) 112 (67.5) 483 (67.2) 177 (68.3)
History of medications use
β-blockers 467 (24.9) 174 (24.9) 41 (25.2) 0.480 190 (27.3) 62 (25.6) 0.197
CCBs 445 (23.7) 173 (24.6) 27 (16.8) 0.054 191 (27.4) 54 (22.4) 0.197
Baseline laboratory test
LVEF, % 61 (56-65) 62 (58-66) 60 (55-66) 0.027 62 (58-66 ) 59 (53-63) ＜0.001
Total cholesterol, mmol/L 4.12 (3.46-4.92) 4.03 (3.39-4.89) 4.28 (3.54-5.24) 0.005 4.11 (3.48-4.83) 4.31 (3.6-5.03) 0.037
Triglyceride, mmol/L 1.51 (1.1-2.21) 1.45 (1.05-2.11) 1.58 (1.09-2.34) 0.121 1.54 (1.12-2.24) 1.64 (1.14-2.32) 0.335
HDL-C, mmol/L 1 (0.86-1.16) 1.01 (0.86-1.18) 1.03 (0.9-1.19) 0.267 0.98 (0.86-1.14) 0.96 (0.84-1.11) 0.202
LDL-C, mmol/L 2.44 (1.9-3.09) 2.36 (1.81-3.04) 2.64 (1.99-3.25) 0.005 2.42 (1.94-3.03) 2.61 (1.92-3.32) 0.073
Creatinine, mmol/L 73.6 (64.75-83.7) 71.9 (63.8-82.5) 70.6 (60.9-81.75) 0.402 74.65 (66.1-84.7) 74.6 (65-84) 0.875
Hemoglobin A1C, mmol/L 6.1 (5.6-7) 6 (5.6-6.9) 6.1 (5.6-7.23) 0.345 6 (5.6-6.98) 6.3 (5.7-7.55) 0.026
hs-CRP, mg/L 1.99 (0.77-6.18) 1.3 (0.59-3.99) 2.56 (0.94-12.33) ＜0.001 2.09 (0.86-6.21) 4.36 (1.59-13.25) ＜0.001
Diagnosis 0.020 0.011
UA 1105 (58.9) 466 (63.7) 87 (52.4) 423 (58.8) 129 (49.8)
NSTEMI 353 (18.8) 132 (18.1) 36 (21.7) 136 (18.9) 49 (18.9)
STEMI 417 (22.2) 133 (18.2) 43 (25.9) 160 (22.3) 81 (31.3)
Procedures
PCI 1180 (62.9) 410 (56.1) 124 (74.7) ＜0.001 457 (63.6) 189 (73.0) 0.006
CABG 122 (6.5) 63 (8.6) 7 (4.2) 0.056 41 (5.7) 11 (4.2) 0.371
Number of coronary artery lesions 0.301 0.246
0 165 (8.8) 73 (10) 16 (9.6) 51 (7.1) 25 (9.7)
1 502 (26.8) 209 (28.6) 38 (22.9) 195 (27.1) 60 (23.2)
≥ 2 1208 (64.4) 449 (61.4) 112 (67.5) 473 (65.8) 174 (67.2)
Medications on discharge
Aspirin 1829 (97.5) 712 (97.4) 164 (98.8) 0.283 700 (97.4) 253 (97.7) 0.776
P2Y12 inhibitors 1720 (91.7) 662 (90.6) 154 (92.8) 0.370 664 (92.4) 240 (92.7) 0.870
β-blockers 1450 (77.3) 539 (73.7) 143 (86.1) ＜0.001 542 (75.4) 226 (87.3) ＜0.001
ACEIs/ARBs 1161 (61.9) 431 (59.0) 90 (54.2) 0.264 455 (63.3) 185 (71.4) 0.018
Statins 1847 (98.5) 721 (98.6) 164 (98.8) 0.869 708 (98.5) 254 (98.1) 0.663
CCBs 395 (21.1) 143 (19.6) 26 (15.7) 0.246 174 (24.2) 52 (20.1) 0.177

The data is presented as mean±SD, median (first quartile to third quartile), or n (%). Abbreviations: ACEI, angiotensin-converting enzymes inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; CABG, coronary artery bypass grafting; CCBs, Calcium channel blockers; Hs-CRP, High sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NSTEMI Non-ST-segment-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment-elevation myocardial infarction; UA, unstable angina.

In patients with ACS, those in the HNRHR group had significantly higher AHI, ODI, T90, and Epworth Sleepiness Scale than in patients in the non-HNRHR group. In addition, the patients with HNRHR were in a more severe state of hypoxia (Supplementary Table 2). The correlation between nighttime RHR and AHI is shown in Supplementary Fig.1. When further testing the effect of HNRHR on sleep monitoring indicators, the sleep characteristics differed between the OSA and non-OSA groups. In the OSA group, sleep monitoring indicators were worse in patients in the HNRHR group compared with those in the non-HNRHR group (Table 2).

Supplementary Table 2.Result of sleep study in HNRHR versus non-HNRHR groups

Variables Non-HNRHR (n= 1450) HNRHR (n= 425) P-value
Sleep study
AHI, events/h 14.8 (7.8-28.1) 20.1 (9.0-36.5) ＜0.001
ODI, events/h 14.6 (8.4-26.7) 20.3 (11.1-36.7) ＜0.001
Minimum SaO2, % 85.0 (81.0-88.0) 84.0 (78.0-88.0) ＜0.001
Mean SaO2, % 94.0 (93.0-95.0) 93.0 (92.0-94.0) ＜0.001
T90, % 2.0 (0.3-8.0) 5.0 (1.0-15.0) ＜0.001
Epworth Sleepiness Scale 7.0 (4.0-11.0) 9.0 (4.8-12.0) 0.003

The data are presented as median (first quartile to third quartile); AHI, apnea-hypopnea index; ODI, oxygen desaturation index; SaO2, arterial oxygen saturation; T90=percentage of Time with SaO2 ＜90%

Supplementary Fig.1.

correlation between mean night-time resting heart rate and apnea-hypopnea index

Table 2.Result of sleep study in HNRHR versus non-HNRHR groups categorized by OSA

Variables

ALL

(N = 1875)

 Non-OSA OSA

non-HNRHR

(n = 731)

HNRHR

(n = 166)

p-value

non-HNRHR

(n = 719)

HNRHR

(n = 259)

p-value
Sleep study
AHI, events/h 15.7 (8-29.7) 7.8 (4.3-10.9) 7.1 (3.7-10.4) 0.176 28.2 (20.6-40.2) 32.4 (21.6-50.4) 0.002
ODI, events/h 16.1 (8.8-28.5) 8.6 (4.9-11.7) 9.1 (4.8-13.1) 0.118 26.7 (19.5-37.5) 32.2 (21.7-47.7) ＜0.001
Minimum SaO2, % 85 (81-88) 88 (85-90) 87 (83-89) 0.289 83 (78-86) 82 (75-86) 0.024
Mean SaO2, % 94 (93-95) 95 (93-95) 94 (93-95) ＜0.001 93 (92-94) 93 (92-94) ＜0.001
T90, % 2.1 (0.4-10) 0.5 (0.1-2.1) 1.0 (0.1-6.0) 0.007 5.75 (2.0-14.9) 9 (2.5-21.0) ＜0.001
Epworth Sleepiness Scale 7 (4-11) 6 (3-10) 7.5 (3-11.8) 0.222 8 (4-12) 9 (6-13) 0.026

The data is presented as median (first quartile to third quartile); AHI, apnea-hypopnea index; ODI, oxygen desaturation index; SaO2, arterial oxygen saturation; T90=percentage of Time with SaO2 ＜90%

Outcomes in the Overall Population According to OSA and RHR

The mean median follow-up time was 2.9 years (1.5–3.5). Among patients with ACS, the presence of OSA was associated with a higher rate of MACCE compared with those without OSA in the overall population (log-rank, P=0.048; Supplementary Fig.2). Kaplan–Meier analysis showed that the cumulative incidence of MACCE was significantly higher in the HNRHR group than in the non-HNRHR group (log-rank, P=0.002; Fig.2a). After adjustment for the baseline risk of cardiovascular events, patients with HNRHR were strongly associated with a higher rate of MACCE than patients with non-HNRHR (HR: 1.4, 95% CI: 1.06–1.87, P=0.018; Table 3).

Supplementary Fig.2.

Kaplan-Meier curves for the analysis of cardiovascular events in OSA versus non-OSA group

Fig.2. High night-time resting heart rate (HNRHR) and risk of major adverse cardiovascular and cerebrovascular event (MACCE) in a) the overall population and by OSA: b) OSA; c) non-OSA

Kaplan–Meier estimates for MACCE between HNRHR and non-HNRHR groups in the overall population and by OSA

Table 3.Cox regression analyses evaluating the association between HNRHR and cardiovascular events group by OSA

Model 1 Model 2 Model 3
HR (95% CI) P-value HR (95% CI) p-value HR (95% CI) p-value
MACCE
Overall 1.54 (1.17-2.03) 0.002 1.54 (1.17-2.03) 0.002 1.40 (1.05-1.87) 0.02
Non-OSA 1.27 (0.79-2.03) 0.32 1.21 (0.75-1.96) 0.43 1.20 (0.73-1.96) 0.48
OSA 1.65 (1.17-2.32) 0.004 1.68 (1.19-2.38) 0.003 1.54 (1.06-2.23) 0.02
Cardiovascular death
Overall 1.61 (0.73-3.53) 0.24 1.67 (0.76-3.68) 0.20 1.04 (0.42-2.56) 0.93
Non-OSA 0.77 (0.17-3.45) 0.73 0.76 (0.17-3.41) 0.72 0.55 (0.12-2.56) 0.44
OSA 2.49 (0.90-6.85) 0.08 2.74 (0.99-7.59) 0.05 1.75 (0.50-6.19) 0.38
Hospitalization for myocardial infarction
Overall 1.38 (0.75-2.56) 0.30 1.25 (0.66-2.36) 0.49 1.11 (0.57-2.15) 0.76
Non-OSA 0.99 (0.29-3.43) 0.99 0.67 (0.15-2.96) 0.60 0.60 (0.13-2.73) 0.51
OSA 1.43 (0.70-2.96) 0.33 1.40 (0.68-2.92) 0.37 1.31 (0.61-2.82) 0.49
Stroke
Overall 1.66 (0.86-3.21) 0.13 1.72 (0.89-3.32) 0.11 1.74 (0.87-3.48) 0.12
Non-OSA 1.42 (0.46-4.34) 0.54 1.39 (0.45-4.26) 0.57 1.66 (0.53-5.24) 0.39
OSA 1.70 (0.75-3.89) 0.21 1.79 (0.78-4.11) 0.17 2.17 (0.88-5.38) 0.09
Ischemia-driven revascularization
Overall 1.27 (0.89-1.83) 0.19 1.23 (0.85-1.77) 0.28 1.14 (0.78-1.67) 0.50
Non-OSA 1.30 (0.72-2.35) 0.39 1.20 (0.65-2.21) 0.56 1.17 (0.05-3.91) 0.62
OSA 1.19 (0.75-1.88) 0.46 1.16 (0.73-1.84) 0.53 1.08 (0.66-1.75) 0.77
Hospitalization for heart failure
Overall 1.16 (0.42-3.16) 0.78 1.16 (0.42-3.19) 0.77 0.94 (0.32-2.79) 0.91
Non-OSA 0.60 (0.08-4.47) 0.63 0.57 (0.07-4.54) 0.60 0.43 (0.05-3.45) 0.53
OSA 1.62 (0.47-5.54) 0.44 1.70 (0.50-5.84) 0.40 1.15 (0.31-4.33) 0.84

HR=hazard ratio; MACCE, major adverse cardiovascular and cerebrovascular event including cardiovascular death, MI, stroke, ischemia-driven revascularization, or hospitalization for heart failure. OSA obstructive sleep apnea. Model 1 = unadjusted model; Model 2 = adjusted for age, sex and BMI; Model 3 = adjusted for age, sex, BMI, current smoking, history of hypertension, diabetes, dyslipidemia, prior myocardial infarction, prior stroke, clinical presentation (STEMI vs NSTE-ACS), left ventricular ejection fraction, history of beta-blocker administration and apnea-hypopnea index.

Outcomes of Patients with HNRHR versus Non-HNRHR Stratified by OSA

In the OSA group, Kaplan–Meier analysis showed that MACCE was significantly elevated in the HNRHR group than in the non-HNRHR group (log-rank, P=0.004; Fig.2b). In the non-OSA group, there was no difference in the incidence of MACCE in the HNRHR group compared with the non-HNRHR group (log-rank, P=0.323; Fig.2c). After adjusting for demographics, LVEF, medical history, history of β-blocker administration, and AHI, it was found that HNRHR was associated with an increased risk of MACCE in the OSA group (HR: 1.56, 95% CI: 1.09–2.23, P=0.014; Table 3) but not in the non-OSA group (HR: 1.13, 95% CI: 0.69–1.84, P=0.63; Table 3). No significant differences were observed between the HNRHR and non-HNRHR groups in individual cardiovascular events (Table 3). The crude numbers of events are listed in Supplementary Table 3.

Supplementary Table 3.Crude Number of Events in HNRHR versus non-HRHR groups categorized by OSA

Variables Non-OSA OSA
non-HNRHR (n= 731) HNRHR (n= 166) non-HNRHR (n= 719) HNRHR (n= 259)
MACCE 84 (11.5) 22 (13.3) 91 (12.7) 51 (19.7)
Cardiovascular death 12 (1.6) 2 (1.2) 8 (1.1) 7 (2.7)
Hospitalization for myocardial infarction 15 (2.1) 3 (1.8) 22 (3.1) 11 (4.2)
Stroke 13 (1.8) 4 (2.4) 15 (2.1) 9 (3.5)
Ischemia-driven revascularization 51 (7.0) 14 (8.4) 62 (8.6) 26 (10.0)
Hospitalization for heart failure 9 (1.2) 1 (0.6) 7 (1.0) 4 (1.5)

Data are presented as n (%).HNRHR, high night-time resting heart rate; MACCE, major adverse cardiovascular and cerebrovascular event; OSA, obstructive sleep apnea.

Discussion

In this study with an established population of patients with ACS, nearly a quarter of these patients have HNRHR and elevated RHR significantly increased the incidence of MACCE in these patients. In the OSA-stratified analyses, RHR was associated with an increased risk of MACCE in the OSA group but not in the non-OSA group. Our study identifies a clinically high-risk population of patients with ACS and highlights the importance of heart rate control particularly in those with OSA.

RHR is strongly associated with the prognosis of patients with ACS. A large prospective cohort study found that patients with a heart rate of ≥ 70 bpm had two times the increased risk of long-term cardiovascular mortality compared with patients with a heart rate of ＜70 bpm20). Similarly, data from a meta-analysis based on 11 studies showed that ＞70 bpm was significantly associated with in-hospital and long-term mortality in patients with ACS21). Current guidelines emphasize heart rate control for ACS management, along with β-blockers recommended for long-term heart rate control in almost all patients with ACS22). Studies have demonstrated that the use of β-blockers can improve outcomes in these patients23). However, some studies reported that post-discharge β-blocker use failed to improve the incidence of major adverse cardiovascular events at 6 and 12 months in the same group of patients24, 25). Our study showed that the use of β-blockers in patients with ACS on discharge was nearly 80%. In particular, the proportion of patients using β-blockers was higher in the HNRHR group than in the non-HNRHR group. Despite the strong correlation with the prognosis of patients with ACS, a significant proportion of patients have an elevated RHR. Our study showed that 22.7% of patients with ACS had an elevated RHR of ≥ 70 bpm. A potential reason for the difficulty in controlling RHR in some patients with ACS may be the influence of other comorbidities such as diabetes, hypertension, hyperlipidemia, heart failure, and OSA. Studies have demonstrated that in patients with ACS, patients with a high RHR have a higher prevalence of hypertension and are independently associated with the occurrence of adverse cardiovascular events26). Therefore, an in-depth analysis of the relationship between RHR and cardiovascular comorbidity in patients with ACS and its impact on the prognosis could help to improve the clinical outcomes in these patients.

OSA is frequent in patients with ACS, with prevalence varying from 36% to 63% across ethnic groups27), and is an independent risk factor for the long-term prognosis of patients with ACS28). Jan et al. found that patients with moderate to severe OSA had elevated sympathetic activity, increased blood pressure, and elevated RHR29). This was confirmed in our study, where patients in the OSA group had a faster RHR and a higher proportion of HNRHR. Elevated RHR is a marker of increased sympathetic activity and a major cardiovascular disease risk factor30). Alterations in autonomic function may be a key mediator linking OSA and cardiovascular disease. Cristina et al. have shown that the main response to increased sympathetic activity in patients with OSA is a characteristic increase in heart rate31). In an OSA cohort, Xu et al. found that both nighttime hypoxia and elevated mean heart rate were independent predictors of adverse cardiovascular events in patients with OSA32). The pathophysiological mechanism behind autonomic dysfunction and cardiovascular outcomes may have multiple pathways. Previous research has confirmed that heightened sympathetic drive directly elevates heart rate, cardiac output, and vascular resistance, which leads to hypertension and myocardial ischemia33). Additionally, sympathetic hyperactivity triggers inflammatory and oxidative stress pathways that accelerate atherogenesis34). In patients with metabolic syndrome, sympathetic overactivation has been linked to metabolic derangements, such as insulin resistance, that compound cardiovascular risk35). All of this suggests that the autonomic nervous system is strongly associated with adverse cardiovascular outcomes. In the present study, we found that HNRHR was associated with an increased risk of MACCE in the OSA group but not in the non-OSA group. A potential explanation may be the changes in physiological indicators caused by repeated upper airway obstruction during sleep, including reduced SaO2, hypercapnia, microarousals, and changes in thoracic pressure, all of which can activate the autonomic nervous system and are further reflected in an increased heart rate during sleep36), representing the severity of the respiratory event and the degree of autonomic nervous system reactivity. For non-OSA patients, the reason for the lack of significant effect of HNRHR on MACCE could be that this group of patients has fewer underlying diseases. In our study, we showed that the proportion of patients with HNRHR who have obesity (BMI ≥ 28 kg/m2) and diabetes in the non-OSA group was not significantly different compared with non-HNRHR patients. This group of patients has a homogeneous disease background and may have a greater clinical benefit from the use of heart rate control drugs.

Prior research has elucidated several pathways through which both OSA and tachycardia can promote thromboembolic cerebral infarction. Intermittent hypoxemia in OSA can elicit systemic inflammation, oxidative stress, and endothelial dysfunction that creates a hypercoagulable state37). Independent of OSA, elevated heart rate itself induces irregular blood flow patterns and hemodynamic shear stress that can disrupt atherosclerotic plaques and provoke thrombus formation38, 39). Additionally, OSA exacerbates other risk factors for stroke such as hypertension, diabetes, and dyslipidemia, which synergistically accelerate cerebral small vessel disease in the presence of tachycardia40). Taken together, these potential mechanisms provide biological plausibility for the association between OSA, heightened heart rate, and increased stroke events. However, in the present study, we found that there was no significant difference in stroke events (P=0.12 in the overall population and P=0.09 in the OSA group) when analyzed individually. This may be due to the relatively small sample size of the population in which the incidence of stroke is low, at about 2%.

In this article, we found that patients with ACS experiencing OSA need more attention to their RHR and that emphasis should be placed on controlling RHR in clinical practice. However, many issues such as the target heart rate for patients with OSA and how to control heart rate with appropriate drugs and other modalities remain unresolved and need to be further investigated in future clinical trials.

Limitations

This study has several potential limitations. First, while the study utilized a portable sleep apnea monitor, which might underestimate certain results, it’s worth noting that using such devices is a commonly accepted and prevalent method in past research41, 42). Second, this study recruited predominantly East Asian patients, so it may be limited when generalized to patients with other ethnic or racial backgrounds. Furthermore, the data on formal sleep center follow-up visits and OSA treatment adherence after hospital discharge were not included, thus the effect of OSA treatment on MACCE could not be assessed in this study. Finally, this study was completed based on a prospective cohort study; therefore, the extent of the association between exposure and outcome may have been systematically overestimated compared with the results of randomized controlled trials.

Conclusion

Among patients with ACS, the incidence of MACCE was significantly higher in those with OSA in the HNRHR group than in those in the non-HNRHR group, suggesting that HNRHR associated with OSA should be given much more attention to identifying patients with clinical high-risk ACS. This discovery highlights the importance of heart rate control to reduce cardiovascular risk in patients with ACS experiencing OSA and provides a recommendation to future clinical trials for better high-risk patient screening.

Acknowledgements

Thanks to Drs Ruifeng Guo, Zexuan Li, and Ge Wang for collecting study data (Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China).

Author Contributions

Qingjie Xin: Conceptualization, Writing - Original Draft, Data Curation; Wei Gong: Writing - Review & Editing, Supervision; Wen Zheng: Formal analysis, Data Curation; Xiao Wang: Writing - Original Draft, Methodology; Yan Yan: Validation; Bin Que: Software; Siyi Li, Zekun Zhang, Xiuhuan Chen, Yun Zhou, Jingyao Fan: Formal analysis, Resources; Hui Ai, Shaoping Nie: Supervision, Funding acquisition.

Funding

The study has been funded by National Natural Science Foundation of China (grant numbers 82270258, 81970292, 82100260), National Key Research & Development Program of China (grant number 2020YFC2004800).

Availability of Data and Materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate The study was approved by the Institutional Review Board of Beijing Anzhen Hospital, Capital Medical University (2013025) and all patients provided written informed consent.

Consent for Publication

All the authors consent to the publication of the manuscript.

Financial/Nonfinancial Disclosures

None.

References
 

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