Abstract
Study Objectives:
In coronary artery bypass grafting (CABG), abnormal cardiac repolarization is associated with adverse cardiovascular events that can be measured via the QTc interval. We investigated the impact of obstructive sleep apnea on the change in repolarization after CABG and the association of change in repolarization with the occurrence of major adverse cardiac and cerebrovascular events.
Methods:
A total of 1,007 patients from 4 hospitals underwent an overnight sleep study prior to a nonemergent CABG. Electrocardiograms of 954 patients (median age: 62 years; male: 86%; mean follow-up: 2.1 years) were acquired prospectively within 48 hours before CABG (T1) and within 24 hours after CABG (T2). QTc intervals were measured using the BRAVO algorithm by Analyzing Medical Parameters for Solutions LLC. The change in T2 from T1 for QTc (ΔQTc) was derived, and Cox regression was performed.
Results:
Compared with those without, patients who developed major adverse cardiac and cerebrovascular events (n = 115) were older and had (1) a higher prevalence of smoking, hypertension, diabetes mellitus, and chronic kidney disease; (2) a higher apnea-hypopnea index and oxygen desaturation index; and (3) a smaller ΔQTc. Cox regression analysis demonstrated a smaller ΔQTc to be an independent risk factor for major adverse cardiac and cerebrovascular events (hazard ratio: 0.997; P = .032). In the multivariable regression model, a higher oxygen desaturation index was independently associated with a smaller ΔQTc (correlation coefficient: −0.58; P < .001).
Conclusions:
A higher preoperative oxygen desaturation index was an independent predictor of a smaller ΔQTc. ΔQTc within 24 hours after CABG could be a novel predictor of occurrence of major adverse cardiac and cerebrovascular events at medium-term follow-up.
Clinical Trial Registration:
Registry: ClinicalTrials.gov; Name: Undiagnosed Sleep Apnea and Bypass OperaTion (SABOT); URL: https://classic.clinicaltrials.gov/ct2/show/NCT02701504; Identifier: NCT02701504.
Citation:
Teo YH, Yong CL, Ou YH, et al. Obstructive sleep apnea and temporal changes in cardiac repolarization in patients undergoing coronary artery bypass grafting. J Clin Sleep Med. 2024;20(1):49–55.
Keywords: coronary artery disease surgery, cardiac surgery, cardiac procedures and therapy, cardiac surgery, cardiac procedures, cardiac risk factors, prevention
BRIEF SUMMARY
Current Knowledge/Study Rationale: In coronary artery bypass grafting, abnormal cardiac repolarization is associated with adverse cardiovascular events. We aimed to investigate the impact of obstructive sleep apnea on the change in repolarization after coronary artery bypass grafting and the association of change in repolarization with the occurrence of major adverse cardiac and cerebrovascular events.
Study Impact: Compared with those without, patients who developed major adverse cardiac and cerebrovascular events had more severe obstructive sleep apnea as measured by the oxygen desaturation index, and a smaller ΔQTc between pre– and 24 hours post–coronary artery bypass grafting. Further studies should explore the possible intermediate role of abnormal cardiac repolarization in the causal pathway of obstructive sleep apnea and adverse cardiovascular outcomes.
INTRODUCTION
Obstructive sleep apnea (OSA) is a highly prevalent chronic sleep disorder affecting 40–80% of patients with cardiovascular disease.1,2 The recurrent upper-airway obstructive events during sleep in patients with OSA results in intermittent hypoxia and autonomic fluctuation,3,4 which could contribute to adverse myocardial remodeling.5 In patients undergoing coronary artery bypass grafting (CABG), OSA is present in 50% and untreated OSA is associated with an increased risk of cardiovascular complications.6–8
Interpretation of surface electrocardiogram (ECG) intervals has been shown to predict malignant cardiac arrhythmias.6 OSA was recently found to be associated with abnormal cardiac repolarization on the basis of prolonged QTc interval.7 In a previous study, patients with untreated OSA were found to have a longer QTc interval, suggesting a potentially higher risk of future major adverse cardiac and cerebrovascular events (MACCEs).8,9 Furthermore, changes in cardiac repolarization have been linked to potentially lethal arrhythmias.10,11 However, these studies assessed cardiac repolarization at 1 time point only. There is a scarcity of data on the impact of untreated OSA on the change in cardiac repolarization in patients undergoing CABG. Furthermore, the relationship between OSA, abnormal cardiac repolarization, and the occurrence of MACCEs in patients undergoing CABG has not been examined.
In the Sleep Apnea and Bypass OperaTion (SABOT) prospective cohort study, we previously reported that sleep apnea was independently associated with increased MACCEs in patients undergoing CABG. In this ancillary study of the SABOT cohort, we aimed to investigate the impact of OSA on the change in repolarization after CABG and the association of change in repolarization with the occurrence of MACCEs. We hypothesized that OSA is independently associated with abnormal repolarization, which, in turn, is associated with a higher incidence of MACCEs.
METHODS
Study design
The study design and findings of the SABOT study (NCT02701504) have been previously published.12 In brief, the SABOT study aimed to evaluate the association between sleep apnea and MACCEs, defined as a composite of cardiovascular death, myocardial infarction, stroke, and unplanned revascularization. It is a prospective cohort study of 1,007 patients referred from 4 public hospitals to undergo a nonemergent CABG at a tertiary cardiac center. As per routine clinical protocol, all patients undergoing nonemergent CABG were admitted at least 1 day prior to surgery; all recruited patients underwent an overnight sleep study on the night before CABG. OSA was demonstrated to be independently associated with increased MACCEs in patients undergoing CABG. The study protocol was approved by the local institutional review board (Domain Specific Review Board-C, National Healthcare Group), and all participants gave written informed consent.
The inclusion criteria comprised patients aged 18–90 years who were scheduled to undergo nonemergent CABG, defined as an interval of at least 24 hours between the decision to perform CABG and the procedure. Patients were excluded if they had received continuous positive airway pressure therapy or other OSA therapies, mechanical ventilation or intra-aortic balloon pump for cardiogenic shock, or oxygen therapy for a heart failure exacerbation; were deemed high risk for malignant arrhythmia; were started on long-term α-blocker therapy; or previously had severe chronic pulmonary disease.
In the American Academy of Sleep Medicine OSA guidelines, OSA diagnosis is made with an apnea-hypopnea index(AHI) ≥ 5 events/h in symptomatic patients or an AHI ≥ 15 events/h in asymptomatic patients. As our cohort comprises patients electively admitted for CABG rather than referred from an OSA clinic, we utilized an AHI >15 events/h for OSA diagnosis as per previous cardiovascular studies.13,14 All patients were followed prospectively (mean follow-up duration: 2.1 years) through a combination of clinical consults, electronic medical records, and/or telephone calls.
Between November 2013 and December 2018, a total of 1,007 patients completed the study. OSA was diagnosed in 513 patients (50.9%). The AHI is measured by the number of apneas or hypopneas recorded during the study per hour of sleep. The severity of sleep apnea can similarly be measured by the respiratory disturbance index (RDI), which is the number of apneas, hypopneas, and respiratory events per hour of sleep. A higher oxygen desaturation index (ODI) and longer duration of lower oxygen saturation (SpO2) can also supplement information on increased severity of OSA. The ODI is defined as the average number of desaturation episodes occurring per hour, with desaturation episodes defined as a decrease in the mean SpO2 of ≥ 3% that lasts for at least 10 seconds.15 An SpO2 < 90% is defined as the cumulative time with SpO2 below 90% in total sleep time.13 All patients who underwent a sleep study were informed of the results by mail within 1 month.
ECG measurement
ECGs were acquired prospectively within 48 hours before CABG (T1) and within 24 hours after CABG (T2). A total of 954 patients survived the initial 24 hours and had quality ECGs for analysis. ECG measurements were derived using the BRAVO algorithm by Analyzing Medical Parameters for Solutions (AMPS) LLC, a well-validated software for automated ECG intervals analysis. Cardiac repolarization parameters that were analyzed comprised the QTc interval.16 QT intervals were measured in 3 consecutive heart beats in 1 lead, preferentially lead II (75%), followed by lead V5 (25%). QT was corrected for heart rate using Bazett’s formula. The change in T2 from T1 for QTc (ΔQTc) was derived.
Statistical analysis
Categorical variables are summarized as frequencies and percentages, and Pearson’s χ2 test for independence was used to compare the categorical variables among the groups based on the presence of MACCEs. Continuous variables following normal distribution were summarized as means and standard deviations and compared using 2-sample t tests based on the presence of MACCEs. Variables that did not follow normal distributions are summarized as medians with interquartile ranges and compared using Mann-Whitney U test.
Correlation analyses were carried out to identify possible relationships between risk factors and cardiac repolarization parameters. Results are presented as correlation coefficients and P values. Significant risk factors (P < .05) in the correlation analyses were entered into the multiple linear regression analysis and a backward selection method was applied.
For cardiac repolarization parameters with a significant association with the presence of MACCEs (P < .05), Cox regression analysis was utilized to elucidate the hazard ratios and 95% confidence intervals of cardiac repolarization parameters in predicting the presence of MACCE outcome with the adjustment of age, sex, smoking, diabetes mellitus, hypertension, chronic kidney disease, and AHI. The backward selection method was applied to obtain the final model.
All analyses were conducted using IBM SPSS Statistics 27 (IBM Corporation, Armonk, NY) assuming a 2-sided test with a 5% level of significance. P values < .05 were considered statistically significant.
RESULTS
Cardiac repolarization parameters at baseline
Before CABG (T1), compared with those with shorter QTc, patients with a longer QTc were more likely to be female, have a higher body mass index, larger waist circumference, higher EuroSCORE, lower left ventricular ejection fraction, higher pulmonary artery systolic pressure, and were more likely to have diabetes mellitus and chronic kidney disease (Table 1). Compared with those with shorter QTc, patients with a longer QTc were also more likely to have OSA of greater severity, including a higher AHI, higher RDI, higher ODI, and a longer duration of arterial SpO2 < 90% (Table 1). After adjusting for the effects of confounding variables, SpO2 < 90% was shown to be independently associated with a longer QTc (correlation coefficient: 0.478; P = .001) (Table 2).
Table 1.
Association of baseline characteristics with baseline cardiac repolarization parameters.
| Variables | QTc |
|---|---|
| Age | 0.038 (.240) |
| Sex | −0.134 (< .001) |
| Ethnicity | (.792) |
| Systolic blood pressure | 0.034 (.288) |
| Diastolic blood pressure | −0.004 (.905) |
| Body mass index | 0.068 (.037) |
| Neck circumference | 0.004 (.901) |
| Waist circumference | 0.123 (< .001) |
| Smoking | (.913) |
| Hyperlipidemia | 0.011 (.727) |
| Hypertension | −0.010 (.758) |
| Diabetes mellitus | 0.144 (< .001) |
| Family history of premature coronary disease | −0.075 (.021) |
| Previous myocardial infarction | 0.007 (.837) |
| Previous percutaneous coronary intervention | −0.026 (.429) |
| Previous coronary artery bypass grafting | −0.024 (.459) |
| Stroke/transient ischemic attack | −0.012 (.713) |
| Chronic kidney disease | 0.123 (< .001) |
| Chronic kidney disease on dialysis | 0.134 (< .001) |
| Pre-existing atrial fibrillation | −0.004 (.891) |
| Pacemaker in situ | −0.009 (.777) |
| Implantable cardioverter defibrillator in situ | −0.032 (.318) |
| AHI | 0.174 (< .001) |
| RDI | 0.149 (< .001) |
| ODI | 0.191 (< .001) |
| Sleep duration | 0.008 (.794) |
| Duration SpO2 < 90% | 0.149 (< .001) |
| Percentage of sleep SpO2 < 90% | 0.146 (< .001) |
| Clinical presentation | (.091) |
| Number of diseased coronary vessels | (.457) |
| Left main artery stenosis ≥ 50% | −0.033 (.307) |
| Proximal left anterior descending artery stenosis ≥ 50% | 0.024 (.455) |
| SYNTAX score | 0.086 (.178) |
| EuroSCORE | 0.140 (.022) |
| Left ventricular ejection fraction | −0.218 (< .001) |
| Left ventricular end-diastolic internal diameter | 0.186 (< .001) |
| Left ventricular end-systolic internal diameter | 0.231 (< .001) |
| Left ventricular mass index | 0.214 (< .001) |
| Aortic root diameter | −0.038 (.295) |
| Early to late diastolic transmitral flow velocity (E/A) | 0.156 (< .001) |
| Pulmonary artery systolic pressure | 0.157 (< .001) |
Correlation coefficients are reported with P value in parentheses. AHI = apnea-hypopnea index, ODI = oxygen desaturation index, RDI = respiratory disturbance index, SpO2 = arterial oxygen saturation.
Table 2.
Multivariable regression of baseline characteristics with baseline cardiac repolarization parameters (only those with P < .05 in Table 6 were included and then backward selection was applied).
| Variables | QTc |
|---|---|
| Waist circumference | |
| Diabetes mellitus | |
| Chronic kidney disease on dialysis | |
| Duration SpO2 < 90% | 0.478 (P = .001) |
| Left ventricular end-diastolic internal diameter | |
| Left ventricular end-systolic internal diameter |
Correlation coefficients are reported with P value in parentheses (only significant variables are presented). SpO2 = arterial oxygen saturation.
Change in cardiac repolarization parameters
The change in cardiac repolarization intervals in patients undergoing CABG (T2 – T1) is represented in Table 3. Older age, history of previous stroke, chronic kidney disease, more severe sleep apnea (higher AHI, ODI, and severe oxygen desaturation) were associated with smaller ΔQTc.
Table 3.
Association of baseline characteristics with change in cardiac repolarization parameters.
| Variables | Change QTc (T2 – T1) |
|---|---|
| Age | −0.093 (.006) |
| Sex | 0.026 (.436) |
| Ethnicity | (.343) |
| Systolic blood pressure | 0.006 (.863) |
| Diastolic blood pressure | 0.034 (.315) |
| Body mass index | 0.026 (.440) |
| Neck circumference | 0.045 (.180) |
| Waist circumference | −0.022 (.518) |
| Smoking | (.250) |
| Hyperlipidemia | 0.019 (.578) |
| Hypertension | 0.002 (.954) |
| Diabetes mellitus | −0.052 (.123) |
| Family history of premature coronary disease | 0.038 (.262) |
| Previous myocardial infarction | 0.005 (.877) |
| Previous percutaneous coronary intervention | 0.035 (.309) |
| Previous coronary artery bypass grafting | −0.016 (.631) |
| Stroke/transient ischemic attack | 0.075 (.026) |
| Chronic kidney disease | −0.073 (.031) |
| Chronic kidney disease on dialysis | −0.040 (.244) |
| Pre-existing atrial fibrillation | −0.042 (.871) |
| Pacemaker in situ | −0.056 (.099) |
| Implantable cardioverter defibrillator in situ | 0.022 (.508) |
| AHI | −0.110 (.001) |
| RDI | −0.092 (.007) |
| ODI | −0.131 (< .001) |
| Sleep duration | 0.031 (.365) |
| Duration SpO2 < 90% | −0.067 (.047) |
| Percentage of sleep SpO2 < 90% | −0.081 (.017) |
| Clinical presentation | (.302) |
| Number of diseased coronary vessels | (.095) |
| Left main artery stenosis ≥ 50% | −0.023 (.507) |
| Proximal left anterior descending artery stenosis ≥ 50% | −0.023 (.495) |
| SYNTAX score | 0.003 (.968) |
| EuroSCORE | −0.127 (.054) |
| Left ventricular ejection fraction | 0.017 (.640) |
| Left ventricular end-diastolic internal diameter | −0.012 (.750) |
| Left ventricular end-systolic internal diameter | −0.015 (.689) |
| Left ventricular mass index | −0.094 (.026) |
| Aortic root diameter | 0.067 (.075) |
| Early to late diastolic transmitral flow velocity (E/A) | −0.054 (.156) |
| Pulmonary artery systolic pressure | −0.059 (.184) |
Correlation coefficients are reported with P value in parentheses. AHI = apnea-hypopnea index, ODI = oxygen desaturation index, RDI = respiratory disturbance index, SpO2 = arterial oxygen saturation.
After adjusting for the effects of confounding variables, an older age (correlation coefficient: −0.78; P = .007), history of stroke (correlation coefficient: 16.15; P = .029), and higher ODI (correlation coefficient: −0.58; P < .001) were independently associated with a smaller ΔQTc (Table 4).
Table 4.
Multivariable regression of baseline characteristics with change in cardiac repolarization parameters (only those with P < .05 in Table 6 were included and then backward selection was applied).
| Variables | Change QTc (T2 – T1) |
|---|---|
| Age | −0.78 (.007) |
| Stroke/transient ischemic attack | 16.15 (.029) |
| Pre-existing atrial fibrillation | |
| EuroSCORE | |
| ODI | −0.58 (< .001) |
| Percentage of sleep SpO2 < 90% |
Correlation coefficients are reported with P value in parentheses (only significant variables are presented). SpO2 = arterial oxygen saturation, T1 = electrocardiogram acquired prospectively within 48 hours before coronary artery bypass grafting, T2 = electrocardiogram acquired prospectively within 24 hours after coronary artery bypass grafting.
Characteristics of MACCE vs non-MACCE groups
A total of 115 (11%) patients developed MACCEs (MACCE group). Compared with the non-MACCE group, the MACCE group was (1) older; had (2) a higher prevalence of smoking, hypertension, diabetes mellitus, and chronic kidney disease; and (3) higher AHI and ODI (Table 5). Compared with the non-MACCE group, patients with MACCEs also had a longer QTc (P = .012) and smaller ΔQTc (P = .003) (Table 6). Details regarding the diagnostic coronary angiography and echocardiography, CABG operation, and medications upon hospital discharge are included in Table S1 (271.9KB, pdf) , Table S2 (271.9KB, pdf) , and Table S3 (271.9KB, pdf) in the supplemental material.
Table 5.
Baseline demographic and clinical characteristics and sleep study results in MACCE and non-MACCE groups.
| Characteristics | MACCEs (n = 115) | No MACCEs (n = 839) | P |
|---|---|---|---|
| Age, median (IQR), y | 63 (58–69) | 61 (56–67) | .031 |
| Male sex, n (%) | 94 (81.7%) | 728 (86.8%) | .143 |
| Ethnicity, n (%) | |||
| Chinese | 71 (61.7%) | 547 (65.2%) | .146 |
| Malay | 23 (20.0%) | 162 (19.3%) | |
| Indian | 18 (15.7%) | 82 (9.8%) | |
| Others | 3 (2.6%) | 48 (5.7%) | |
| Clinical measurements | |||
| Systolic blood pressure, median (IQR), mm Hg | 126 (112–140) | 125 (111–138) | .536 |
| Diastolic blood pressure, median (IQR), mm Hg | 70 (61–76) | 70 (62–79) | .097 |
| Body mass index, median (IQR), kg/m2 | 25.2 (22.6–27.6) | 24.7 (22.4–27.3) | .579 |
| Neck circumference, median (IQR), cm | 38.5 (37–41.25) | 38.0 (36–40.5) | .208 |
| Waist circumference, median (IQR), cm | 9475 (86.75–102.0) | 92.0 (86.0–99.0) | .072 |
| Cardiovascular risk factors, n (%) | |||
| Smoking | .041 | ||
| 0 | 71 (61.7%) | 413 (49.2%) | |
| 1 | 25 (21.7%) | 251 (29.9%) | |
| 2 | 19 (16.5%) | 175 (20.9%) | |
| Hyperlipidemia | 94 (81.7%) | 684 (81.5%) | .956 |
| Hypertension | 101 (87.8%) | 616 (73.4%) | <.001 |
| Diabetes mellitus | 83 (77.2%) | 459 (54.7%) | <.001 |
| Family history of premature coronary disease | 8 (7.0%) | 68 (8.1%) | .670 |
| Concomitant conditions, n (%) | |||
| Previous myocardial infarction | 52 (45.2%) | 390 (46.5%) | .798 |
| Previous percutaneous coronary intervention | 18 (15.7%) | 192 (22.9%) | .079 |
| Previous coronary artery bypass grafting | 1 (0.9%) | 1 (0.1%) | .227F |
| Stroke/transient ischemic attack | 18 (15.7%) | 99 (11.8%) | .238 |
| Chronic kidney disease* | 38 (33.0%) | 122 (14.5%) | <.001 |
| Chronic kidney disease on dialysis | 12 (10.4%) | 24 (2.9%) | <.001 |
| Pre-existing atrial fibrillation | 6 (5.2%) | 38 (4.5%) | .741 |
| Pacemaker in situ | 0 (0.0%) | 3 (0.4%) | >.999 |
| Implantable cardioverter defibrillator in situ | 1 (0.9%) | 3 (0.4%) | .402 |
| Sleep study results | |||
| AHI, median (IQR), events/h | 20.6 (10.1–41.1) | 14.5 (5.5–28.0) | <.001 |
| RDI, median (IQR), events/h | 23.7 (13.4–44.1) | 18.8 (10.4–31.1) | .003 |
| ODI, median (IQR), events/h | 11.4 (4.3–26.9) | 7.3 (2.1–17.2) | <.001 |
| Sleep duration, median (IQR), h | 6.1 (5.1–7.3) | 6.4 (5.4–7.2) | .184 |
| Duration SpO2 < 90%, median (IQR), min | 0.8 (0.0–15.0) | 0.5 (0.0–4.8) | .089 |
| Percentage of sleep SpO2 < 90%, median (IQR), % | 0.2 (0.0–4.2) | 0.1 (0.0–1.3) | .082 |
| Epworth Sleepiness Scale > 10, n (%) | 16 (14.0%) | 101 (12.1%) | .552 |
| High-risk Berlin Questionnaire, n (%) | 48 (41.7%) | 368 (44.1%) | .636 |
Serum estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. AHI = apnea-hypopnea index, IQR = interquartile range, MACCE = major adverse cardiac and cerebrovascular event, ODI = oxygen desaturation index, RDI = respiratory disturbance index, SpO2 = arterial oxygen saturation.
Table 6.
Cardiac repolarization markers in MACCE and non-MACCE groups (chi-square test with MACCE and non-MACCE as the binary independent groups).
| Variables | MACCEs (n = 115) | No MACCEs (n = 839) | P |
|---|---|---|---|
| QTc (T1) | 444.6 (62.4) | 431.4 (51.1) | .012 |
| QTc (T2) | 469.8 (68.5) | 477.6 (70.5) | .282 |
| Change QTc (T2 – T1) | 24.6 (79.2) | 47.4 (71.3) | .003 |
MACCE = major adverse cardiac and cerebrovascular event, T1 = electrocardiogram acquired prospectively within 48 hours before coronary artery bypass grafting, T2 = electrocardiogram acquired prospectively within 24 hours after coronary artery bypass grafting.
Cox regression analyses of cardiac repolarization parameters and MACCEs
In the univariate model, QTc (T1) was associated with an increased risk of MACCEs (hazard ratio: 1.004; 95% confidence interval: 1.000, 1.006; P = .028). After adjusting for the effects of age, sex, smoking, diabetes mellitus, hypertension, chronic kidney disease, and AHI, the association became nonsignificant (P = .282). On the contrary, in the univariate model comparing the change in cardiac repolarization pre- and post-CABG, the ΔQTc was associated with a decreased risk of MACCEs (hazard ratio: 0.996; 95% confidence interval: 0.994, 0.999; P = .006). After adjusting for the effects of covariates, the ΔQTc was independently associated with a lower risk of MACCEs (hazard ratio: 0.997; 95% confidence interval: 0.994, 1.000; P = .032).
DISCUSSION
In a cohort of 954 patients undergoing a nonemergent CABG, a smaller ΔQTc between pre- and 24 hours post-CABG was associated with a higher incidence of MACCEs at 2.1 years follow-up. A higher preoperative ODI was an independent predictor of a smaller ΔQTc. To the best of our knowledge, this is the first report that ΔQTc within 24 hours after CABG could be a novel predictor of occurrence of MACCEs at medium-term follow-up. CABG is a commonly performed procedure that may reduce infarcts and cardiovascular mortality up to a maximum of 50% by bypassing diseased coronary territories.17 However, there are high perioperative and postoperative risks associated with CABG itself, including atrial fibrillation and hospitalization for heart failure18; therefore, the identification of risk factors for post-CABG adverse outcomes including MACCEs is necessary for implementing preventive measures.
Previous studies have shown that preoperative repolarization measures such as the QTc predict MACCEs in the CABG population.19 Similarly, in our study, we demonstrated that patients with MACCEs have abnormal preoperative repolarization measures as demonstrated by prolonged QTc. Furthermore, we demonstrated that a smaller ΔQTc was associated with an increased risk of MACCEs; ΔQTc can be used as a novel predictor for MACCEs in CABG patients at medium-term follow-up. In our study, the data reviewed were obtained prospectively, and involved a longer observation period of at least 1 year compared to 2 months. This study is the largest and first prospective study to date to demonstrate the association between cardiac repolarization measures and MACCEs.
The latest data from the American Thoracic Society showed that almost 1 billion people in the world are affected by OSA,20 which has been shown to be associated with a higher risk of stroke and cardiovascular morbidity.21 In a retrospective cohort study, patients with OSA were found to have prolonged cardiac repolarization parameters compared with patients without OSA.22 We found that a prolonged QTc was also correlated with OSA severity with indices comprising AHI, RDI, ODI, and SpO2 < 90% at baseline. Adjusting for multiple covariates, we found that more severe OSA as measured by a higher ODI was independently associated with a smaller ΔQTc. However, no correlation was observed between AHI and QTc or ΔQTc. We postulate that the difference between the ODI and AHI findings with QTc could be attributed to the limitations of the AHI parameter. Intermittent hypoxia in OSA is a possible driver of abnormal cardiac repolarization, given the involvement of hypoxia in QT prolongation.23 While the AHI captures the number of apnea events, it does not account for the individual episode’s depth and duration.24 In contrast, by accounting for desaturation episodes, ODI may provide a better predictor of cardiovascular repolarization and MACCEs by accounting for hypoxia. Further studies investigating the impact of OSA on abnormal cardiac repolarization are needed to elucidate the underlying mechanisms. These findings also further support the potential role for screening for OSA in patients scheduled for CABG to identify candidates at high risk of adverse outcomes.
Our study findings should be interpreted in due consideration of the limitations. First, this was an ancillary study of the SABOT cohort, and therefore may not be sufficiently powered to detect differences in cardiac repolarization parameters. Our findings should accordingly be considered exploratory rather than confirmatory. Second, while our findings demonstrate ΔQTc within 24 hours after CABG as a novel predictor for MACCEs at medium-term follow-up, this may not necessarily reflect the risk of MACCEs at other time points. Third, all patients in the SABOT trial underwent nonemergent CABG; thus, we are uncertain whether the same findings would be observed in patients undergoing emergent CABG. Fourth, while we identified that a longer QTc is associated with an increase in the duration of SpO2 < 90%, the duration of hypoxemia associated with apnea events is not known. Fifth, data on the postdischarge optimization of and adherence to medication were not available. Medication optimization and adherence could have unintended implications on the occurrence of MACCEs at medium-term follow-up. Last, we do not have access to the list of QTc-prolonging and QTc-shortening medications that patients took, which may impact the QTc.
CONCLUSIONS
In a cohort of 954 patients undergoing a nonemergent CABG, a smaller ΔQTc during the first 24 hours after CABG is associated with a higher incidence of MACCEs. A higher preoperative ODI is an independent predictor of a smaller ΔQTc. This suggests that change in QTc within 24 hours after CABG could be a novel predictor of occurrence of MACCEs at medium-term follow-up.
DISCLOSURE STATEMENT
All authors approved the final version for submission. Work for this study was supported by a Transition Award and Clinician Scientist Award from the National Medical Research Council of Singapore (award numbers: NMRC/TA/012/2012; NMRC/CSA-INV/002/2015) and the Junior Research Award, National University Health System. Easmed Pte. Ltd. provided support for the overnight sleep studies but had no role in the study design, data interpretation, or manuscript writing. The authors report no conflicts of interest.
ACKNOWLEDGMENTS
The authors are grateful to Easmed Pte. Ltd. For their support in conducting the overnight sleep studies. Author contributions: Y.H.T., C.L.Y., and C.-H.L. were the chief investigators and designed the trial. C.Y.K. and C.-H.L. adjudicated the study end points. C.L.Y. and Y.H.T. monitored the data and performed analyses. C.H.L., Y.H.O., and W.W.T. provided critical feedback on the study design and activities. All authors contributed to the interpretation of the data and drafting of the manuscript and approved the final version for submission.
ABBREVIATIONS
- AHI
apnea-hypopnea index
- CABG
coronary artery bypass grafting
- ECG
electrocardiogram
- MACCE
major adverse cardiac and cerebrovascular event
- ODI
oxygen desaturation index
- OSA
obstructive sleep apnea
- RDI
respiratory disturbance index
- SABOT
Sleep Apnea and Bypass OperaTion
- SpO2
oxygen saturation
- T1
electrocardiogram acquired prospectively within 48 hours before CABG
- T2
electrocardiogram acquired prospectively within 24 hours after CABG
- ΔQTc
change of T2 from T1 for QTc
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