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Abstract
Background: Obstructive sleep apnea (OSA) is associated with increased mortality, for which impaired functional capacity (IFC) has been established as a surrogate. We sought to assess whether IFC is associated with increased mortality in patients with OSA and whether IFC is predictive of increased mortality after accounting for coronary artery disease.
Methods: Patients with OSA who underwent both polysomnography testing and exercise stress echocardiogram were selected. Records were reviewed retrospectively for demographics, comorbidities, stress echocardiographic parameters, and polysomnography data. Univariable and multivariable logistic regression analysis was used to evaluate the association between IFC and overall mortality. We then evaluated the variables associated with IFC in the overall population and in the subgroup with normal Duke treadmill score (DTS).
Results: In our cohort, 404 (26%) patients had IFC. The best predictors of IFC were female sex, history of smoking, ejection fraction less than 55, increased body mass index, presence of comorbidities, abnormal exercise echocardiogram, abnormal heart rate recovery, and abnormal DTS. Compared with those without IFC, patients with IFC were 5.1 times more likely to die (odds ratio [OR], 5.1; 95% confidence interval [CI], 2.5–10.5; P < 0.0001) by univariate analysis and 2.7 times more likely to die (OR, 2.7; 95% CI, 1.2–6.1; P = 0.02) by multivariate analysis, when accounting for heart rate recovery, DTS, and sleep apnea severity. Among those without coronary artery disease, patients with IFC were at significantly increased risk of mortality (OR, 4.3; 95% CI, 1.35–13.79; P = 0.0088) compared with those with preserved functional capacity.
Conclusions: In our OSA population, IFC was a strong predictor of increased mortality. Among those with normal DTS, IFC identified a cohort at increased risk of mortality.
Obstructive sleep apnea (OSA) occurs in approximately 5 to 10% of the population (1, 2). Studies have shown that patients with OSA have a higher mortality compared with those without OSA (3–5). This mortality risk has been attributed to various factors, including an increased incidence of coronary artery disease (CAD) (3–15), stroke (16), and autonomic dysfunction (17), and an increase in motor vehicle accidents from daytime somnolence (18). Impaired functional capacity (IFC) has been shown to be a good surrogate for total mortality in other diseases, but it is unknown if IFC predicts mortality in patients with OSA (21, 22). In addition, although some studies have assessed the association of IFC and autonomic dysfunction in the OSA population, these studies have typically not taken CAD into account, despite its strong association with both IFC and autonomic dysfunction. It remains unknown whether IFC and autonomic dysfunction are associated with OSA if CAD is taken into account.
For our study, we chose a well-characterized cohort of patients with OSA who underwent a stress echocardiogram. Stress echocardiogram was used as the study parameter because it is one of the best methods of diagnosing CAD (23,24) while also providing data on functional capacity. The aims of our study were to evaluate the risk factors associated with IFC in patients with OSA, to determine whether IFC predicts increased overall mortality in patients with OSA, and to explore a possible link between IFC and mortality in a subpopulation of patients with OSA without CAD.
Between 2003 and 2010, 59,466 patients had stress echocardiography performed and 11,256 patients underwent polysomnography (PSG) at our institution. There were 1,533 patients who had both a stress echocardiogram and PSG, and these formed our study population (Figure 1). All patients underwent a structured interview and chart review prior to their stress test. Data regarding demographics, testing indications, symptoms, risk factors, previous cardiac procedures, comorbidities, and medications were recorded. Mortality data were obtained from the social security database and a review of patient medical records.
Figure 1. Overall study population. DTS = Duke treadmill score; IFC = impaired functional capacity; OSA = obstructive sleep apnea; PSG = polysomnography.
[More] [Minimize]All the patients underwent standard in-lab PSG. OSA was defined as an apnea-hypopnea index (AHI) of 5 or more events per hour of sleep and was graded as mild (AHI 5–15), moderate (AHI 16– 30), or severe (AHI > 30).
After a supine resting ECG was obtained, symptom-limited exercise testing was conducted according to a standard protocol. An ischemic ST-segment response was defined as horizontal or down-sloping ST-segment depression of greater than or equal to 1 mm below baseline taken 80 milliseconds after the J-point if there was less than 1 mm of ST-segment depression at baseline. Functional capacity was measured in metabolic equivalents (METs). One MET is 3.5 ml/kg/min of oxygen consumption (19). Patients who had fair or poor functional capacity for age and sex on the basis of a previously validated scheme from our laboratory were defined as having IFC (20). Specific cutoffs for IFC were less than 10, less than 9, less than 8, less than 7, and less than 6 METs for ages less than or equal to 29, 30 to 39, 40 to 49, 50 to 59, and greater than or equal to 60 years, respectively, for women; and less than 11, less than 10, less than 8.5, less than 8, and less than 7 METs for ages less than or equal to 29, 30 to 39, 40 to 49, 50 to 59, and greater than or equal to 60 years, respectively, for men. Immediately after exercise, patients were asked to lie down in a supine position to perform a post stress echocardiogram. Heart rates were continuously monitored by computerized R-R interval. An abnormal left ventricle test was defined as being scarred, ischemic, or nondiagnostic.
The Duke treadmill score (DTS) was accepted as a surrogate marker for the presence of CAD (23, 24) and was calculated as follows: [duration of exercise (in minutes)] − [5 × maximal ST-segment deviation during or after exercise (in millimeters)] − [4 × treadmill angina index (0 = no angina, 1 = nonlimiting angina, 2 = exercise-limiting angina)]. A treadmill exercise score of 5 or greater was considered low risk; –10 to +4, moderate risk; and less than –10, high risk (21).
Two-dimensional echocardiography was performed before and immediately after exercise (22). Images were obtained in left lateral decubitus position with parasternal, long axis, short axis, apical, four chamber, and two chamber views using standard commercially available equipment. Images were interpreted by an attending cardiologist at our institution who was blinded to the study hypothesis, PSG results, and outcomes data. Left ventricular ejection fraction was estimated visually. Qualitative analysis was done in a standard 16-segment model of the left ventricle to identify ischemia and infarction. There were no missing data for left ventricular ejection fraction, exercise hemodynamic variables, or stress echocardiographic variables.
Heart rate recovery (HRR) was measured as the difference between maximal heart rate and 1-minute heart rate immediately after peak exercise. Abnormal HRR was defined as HRR less than or equal to 18 beats/min (23).
Categorical variables are described as number and proportions. Continuous variables are described as mean and SD. Differences between the two groups were tested with the Chi-square test or the Fisher exact test for categorical variables and with the t test or Wilcoxon rank sum test for continuous variables. The association between individual patient variables and outcomes was evaluated with univariable logistic regression analysis. Associations were expressed as odds ratios and their 95% confidence intervals. Variables with a P value less than or equal to 0.2 in univariable analysis were selected for multivariable logistic regression analysis. A P value of less than 0.05 was considered significant. Overall survival was evaluated with life table analysis, and differences between subgroups were evaluated with the log-rank test. SAS 9.2 (Cary, NC) was used for all statistical analyses.
This study had no external funding source.
A total of 1,533 patients met study criteria and were included in the analysis (Figure 1, Table 1). The mean age of our study participants was 54 years, 60% were men (n = 925), 528 (34.5%) patients had mild OSA, 529 (34.5%) had moderate OSA, and 476 (31%) had severe OSA. IFC was present in 404 (26%) patients, and an abnormal DTS was present in 231 patients (15%) (Figure 2).
| Variable | N | IFC | Univariable OR (95% CI) for IFC | P Value | |
|---|---|---|---|---|---|
| Yes (n = 404) | No (n = 1,129) | ||||
| Age, yr | 54.6 (13.0) | 54.3 (10.6) | 1.01 (0.96–1.07)* | 0.6 | |
| Sleep apnea severity, n (%) | 1,533 | 0.2 | |||
| Mild | 528 | 133 (36) | 395 (35) | 1† | |
| Moderate | 529 | 131 (32) | 398 (35) | 1.0 (0.7–1.3) | |
| Severe | 476 | 140 (35) | 336 (30) | 1.2 (0.9–1.6) | |
| Abnormal renal function, n (%) | 4 | 3 (0.7) | 1 (0.1) | 8.4 (0.8–81.4) | 0.2 |
| Smoking, n (%) | 1,489 | 0.02 | |||
| No | 772 | 184 (46) | 588 (52) | 1† | |
| Yes | 717 | 208 (51) | 509 (45) | 1.3 (1.0–1.6) | |
| Hypercholesterolemia, n (%) | 1,482 | 0.02 | |||
| No | 570 | 172 (43) | 398 (35) | 1† | |
| Yes | 912 | 224 (55) | 688 (61) | 0.8 (0.6–1.0) | |
| EF, % | 1,493 | 0.01 | |||
| ≥55 | 1,394 | 355 (88) | 1,039 (92) | 1.7 (1.1–2.7) | |
| <55 | 99 | 37 (9) | 62 (5) | 1† | |
| LV test result, n (%) | 1,484 | <0.0001 | |||
| Normal | 1,247 | 270 (67) | 977 (87) | 1† | |
| Ischemic/scarred | 84 | 34 (8) | 50 (4) | 2.5 (1.6–3.9) | |
| Nondiagnostic | 153 | 83 (21) | 70 (6) | 4.3 (3.0–6.1) | |
| Male, n (%) (vs. female) | 935 | 180 (46) | 745 (66) | 0.4 (0.3–0.5) | <0.0001 |
| Female, n (%) (vs. male) | 598 | 224 (54) | 384 (34) | 2.5 (2.0–3.3) | <0.0001 |
| BMI, kg/m2 | 35.8 (7.3) | 30.8 (5.2) | 2.0 (1.8–2.2) | <0.0001 | |
| BMI category, n (%) | 1,533 | <0.0001 | |||
| Normal (<25) | 153 | 18 (4) | 135 (12) | 1† | |
| Mild obesity (25–29.9) | 458 | 64 (16) | 394 (35) | 1.2 (0.7–2.1) | |
| Moderate obesity (30–39.9) | 759 | 217 (54) | 542 (48) | 3.0 (1.8–5.0) | |
| Severe obesity (≥40) | 163 | 105 (26) | 58 (5) | 13.6 (7.5–24.4) | |
| Diabetes, n (%) | 1,259 | <0.0001 | |||
| No | 1,025 | 230 (57) | 795 (70) | 1† | |
| Yes (DM1 or DM2) | 234 | 110 (27) | 124 (11) | 3.1 (2.3–4.1) | |
| Hypertension, n (%) | 1,503 | <0.0001 | |||
| No | 679 | 143 (35) | 536 (47) | 1† | |
| Yes | 824 | 259 (64) | 565 (50) | 1.7 (1.4–2.2) | |
| Heart rate recovery, n (%) | 1,528 | <0.0001 | |||
| Normal | 1,335 | 306 (76) | 1,029 (91) | 1† | |
| Poor/abnormal | 193 | 97 (24) | 96 (9) | 3.4 (2.5–4.6) | |
| Duke treadmill score, n (%) | 1,533 | <0.0001 | |||
| Normal | 1,235 | 237 (59) | 998 (88) | 1† | |
| Abnormal | 231 | 136 (34) | 95 (8.4) | 5.9 (4.4–8.0) | |
| Noninterpretable | 67 | 31 (8) | 36 (3) | 3.7 (2.2–6.1) | |
Overall, 404 (26%) patients had IFC. The best predictors of IFC by univariable analysis and multivariable analysis are presented in Tables 1 and 2, respectively. By multivariable analysis (Table 2), the best predictors of IFC were abnormal DTS, elevated body mass index (BMI), diabetes mellitus, and female sex.
| Variable | Multivariable OR (95% CI) for IFC | P Value |
|---|---|---|
| BMI, mean (SD) | 2.0 (1.8–2.3) | <0.0001 |
| Duke treadmill score | ||
| Normal | 1* | <0.0001 |
| Abnormal | 5.5 (3.6–8.3) | |
| Noninterpretable | 1.9 (0.9–4.1) | |
| Female (vs. male) | 2.0 (1.4–2.5) | 0.0001 |
| Male (vs. female) | 0.5 (0.4–0.7) | 0.0001 |
| Diabetes | ||
| No | 1* | 0.0001 |
| Yes (DM1 or DM2) | 2.1 (1.4–3.0) | |
| LV test result | ||
| Normal | 1* | 0.0002 |
| Ischemic/scarred | 1.9 (1.0–3.8) | |
| Nondiagnostic | 2.8 (1.7–4.6) | |
| Heart rate recovery | ||
| Normal | 1* | 0.005 |
| Poor/abnormal | 1.9 (1.2–2.9) | |
| Hypercholesterolemia | ||
| No | 1* | 0.01 |
| Yes | 0.7 (0.5–0.9) | |
| EF | ||
| <55 | 1.7 (0.9–3.5) | 0.1 |
| ≥55 | 1* | |
| Smoking | ||
| No | 1* | 0.1 |
| Yes | 1.4 (1.0–1.9) | |
| Hypertension | ||
| No | 1* | 0.2 |
| Yes | 1.3 (0.9–1.8) | |
| Sleep apnea severity | ||
| Mild | 1* | 0.5 |
| Moderate | 0.9 (0.7–1.3) | |
| Severe | 1.1 (0.7–1.7) |
Thirty-three (2.1%) patients died during follow-up (median, 5.5 yr [interquartile range, 3.7–7.9]). To avoid model overfitting, only four variables were studied as predictors of mortality. These variables were: severity of OSA, HRR, DTS, and IFC. Abnormal HRR, abnormal DTS, and IFC were predictive of total mortality by univariable analysis, and patients with IFC were 5.1 times more likely to die than those without IFC (Table 3). By Kaplan-Meier analysis, abnormal DTS (Figure 3A; log rank P < 0.0001) and IFC (Figure 3B; log rank P < 0.0001) were highly predictive of increased mortality. By multivariable analysis (Table 4), only IFC and abnormal DTS were predictive of total mortality. Patients with IFC were 2.7 times more likely to die compared with patients with normal functional capacity (Table 4). Mortality was lowest in patients with normal DTS and normal functional capacity and highest among patients with abnormal DTS and IFC (Figure 3C).
| Variable | N | Overall Mortality | Univariable OR (95% CI) for Overall Mortality | P Value | |
|---|---|---|---|---|---|
| Yes (n = 33) | No (n = 1,500) | ||||
| Functional capacity, n (%) | 1,533 | ||||
| Normal | 1,129 | 12 (36) | 1,117 (74) | 1 | <0.0001 |
| Impaired | 404 | 21 (64) | 383 (26) | 5.1 (2.5–10.5) | |
| Duke treadmill score, n (%) | 1,533 | ||||
| Normal | 1,235 | 14 (42) | 1,221 (81) | 1 | <0.0001 |
| Abnormal | 231 | 16 (49) | 215 (14) | 6.5 (3.1–13.5) | |
| Noninterpretable | 67 | 3 (9) | 64 (4) | 4.1 (1.1–14.6) | |
| Heart rate recovery, n (%) | 1,528 | ||||
| Normal | 1,335 | 23 (70) | 1,312 (88) | 1 | 0.003 |
| Poor/abnormal | 193 | 10 (30) | 183 (12) | 3.1 (1.5–6.7) | |
| Sleep apnea severity, n (%) | 1,533 | 0.2 | |||
| Mild | 528 | 8 (24) | 520 (35) | 1 | |
| Moderate | 529 | 10 (30) | 519 (35) | 1.3 (0.5–3.2) | |
| Severe | 476 | 15 (45) | 461 (31) | 2.1 (0.9–5.0) | |
Figure 3. Kaplan-Meier survival curves comparing Duke treadmill score (DTS) and impaired functional capacity (IFC). FC = functional capacity.
[More] [Minimize]| Variable | Multivariable OR (95% CI) for Overall Mortality | P Value |
|---|---|---|
| Duke treadmill score | ||
| Normal | 1 | 0.003 |
| Abnormal | 4.1 (1.8–9.3) | |
| Noninterpretable | 2.8 (0.8–10.2) | |
| Functional capacity | ||
| Normal | 1 | 0.02 |
| Impaired | 2.7 (1.2–6.1) | |
| Heart rate recovery* | ||
| Normal | 1 | 0.2 |
| Poor/abnormal | 1.6 (0.7–3.7) | |
| Sleep apnea severity | ||
| Mild | 1 | 0.3 |
| Moderate | 1.1 (0.4–2.9) | |
| Severe | 1.9 (0.8–4.7) |
In the overall study population, 1,235 (85%) patients had normal DTS and 231 (15%) had abnormal DTS. Of those with normal DTS, 237 (19.2%) had IFC (see Table E4 in the online supplement). In this cohort with normal DTS, those with IFC had a significantly higher risk of mortality relative to those with normal functional capacity (odds ratio, 4.31; 95% confidence interval, 1.35–13.79; P = 0.0088) (Table 5). Of the 33 deaths, 16 patients had abnormal DTS (3 with normal functional capacity and 13 with IFC) and 14 patients had a normal DTS (7 with normal functional capacity and 7 with IFC). Three of the DTS were noninterpretable, of which two had IFC (Figure 4; Table E1).
| Alive | Dead | Total | |
|---|---|---|---|
| Normal DTS and normal FC | 991 | 7 | 998 |
| Normal DTS and IFC | 230 | 7 | 237 |
| Total | 1,221 | 14 | 1,235 |
Figure 4. The addition of impaired functional capacity (IFC) increases the ability of stress echocardiography to predict mortality in patients with obstructive sleep apnea (n = 33). DTS = Duke treadmill score.
[More] [Minimize]In the cohort with normal DTS, the best predictors of IFC by multivariable analysis included history of smoking, hypertension, hypercholesterolemia, age, abnormal left ventricle test on stress echocardiogram, HRR, female sex, diabetes, and BMI (Table E5).
We report the results from a large database of well-characterized patients with OSA undergoing stress echocardiography, and our findings extend the literature in several important ways. We found that IFC was a strong predictor of increased mortality among patients with OSA. We also found that IFC continued to be a significant predictor of mortality even in the non-CAD population. In addition, we report that a subgroup of patients with OSA with IFC and abnormal DTS had a higher mortality than those with either factor alone.
OSA has been recognized as a risk factor for increased total mortality in several studies (3, 4, 14, 29–35). IFC has been shown to be a strong predictor of all-cause mortality in a diverse patient population (20), and an association between IFC and OSA has also been reported (24). This association has been postulated to be the result of CAD, autonomic dysfunction, obesity, and/or contribution from other comorbidities, such as diabetes and hypertension. This is the first study that shows that IFC is a strong predictor of mortality in a large, well-characterized cohort of patients with OSA.
The high prevalence of CAD in OSA (6–18, 38–45) is believed to be secondary to several mechanisms, including increased inflammation (25–27), endothelial dysfunction (28–30), platelet aggregation abnormalities (31, 32), hypoxia causing nocturnal ischemia (33, 34), and increased sympathetic tone (17). Given this overlap, it is imperative to exclude CAD when studying the factors responsible for IFC and the potential impact of IFC on mortality among patients with OSA. Due to limitations in sample size or patient data, previous studies have been unable to account for this in their analysis. Punjabi and colleagues analyzed a cohort of patients with OSA and found severe sleep-disordered breathing was associated with increased all-cause mortality in men, particularly in the 40- to 70-year age group after accounting for known confounding factors (35). Their study suggested that the increased risk of death might be associated with CAD. We accounted for CAD by using abnormal DTS as a validated surrogate for CAD (23, 24, 46, 47). We found that IFC was a strong predictor of mortality among patients with OSA with normal DTS. This suggests that IFC can predict mortality in patients with OSA even after accounting for CAD. In addition, we identified a cohort of patients with both IFC and abnormal DTS who were at a higher risk of mortality than those having either factor alone. This has significant clinical implications and potentially identifies a previously undescribed high-risk group among patients with OSA referred for cardiac stress testing. These two findings suggest that the addition of IFC may be able to improve the ability of exercise stress testing to predict mortality in patients with OSA when DTS is normal and may also help identify a group of patients at especially high risk when IFC is found among patients with an abnormal DTS. Similar to an earlier study (36), we found that the presence of CAD (as determined by an abnormal DTS in our cohort) was the strongest predictor of survival by multivariable analysis in patients with OSA undergoing exercise stress testing.
In the overall cohort, as expected, abnormal DTS and abnormal stress echocardiogram, which are surrogates for CAD, were important predictors of IFC. Other important predictors of IFC included diabetes, elevated BMI, abnormal HRR, and hypercholesterolemia, whereas hypertension, low ejection fraction, and OSA severity did not predict mortality. These findings are in agreement with previous studies that have looked at IFC and mortality in other disease cohorts (20, 37). Among the cohort with normal DTS, predictors of IFC included increased age, history of smoking, hypercholesterolemia, hypertension, abnormal left ventricle test on stress echocardiogram, and increased BMI, which are all risk factors for CAD. We postulate that IFC may be identifying a group of patients with normal DTS who are at increased risk of future development of CAD (20). As cardiovascular exercise programs improve functional capacity, patients with OSA with IFC may represent a group with potentially modifiable risk factors for mortality. Clinicians should be aware of the role of functional capacity assessment in order for new patient education strategies, which have the potential to impact mortality in patients with OSA, to be adopted.
OSA has been postulated to be associated with autonomic dysfunction. It has been theorized that nocturnal hypoxia may cause increased catecholamine release possibly leading to autonomic dysfunction (38–40), which is known to be associated with mortality (41–43). HRR after stress testing has been well recognized as a measure of autonomic function (44) and a risk factor for adverse clinical outcomes in several disease states (48, 49). Maeder and colleagues (50) studied HRR in patients with OSA and concluded that the severity of OSA, as defined by the AHI, was independently associated with abnormal HRR. Their study did not account for CAD even though the association between HRR and CAD is well known. In our cohort, reduced HRR was a predictor of IFC in patients without CAD. Even though reduced HRR was a predictor of increased mortality on univariable testing, it no longer predicted mortality when abnormal DTS and IFC were taken into account by multivariable analysis.
In our study, age was not a predictor for IFC in patients with OSA. This was an unexpected finding. Prior studies looking at functional capacity have shown age as a strong predictor of IFC (37). It is unclear whether the discrepancy in our results is due to the population being studied, as it only included individuals referred for exercise stress testing.
Major strengths of our study include the large, well-characterized OSA population and the long follow-up period. Our study has some limitations. This is a retrospective study; therefore, stress echocardiography and PSGs were not done concurrently, and the study population composed of only those who were referred for exercise testing may have resulted in a selection bias. Last, we obtained mortality data from the social security database, which is not a real-time database.
We found IFC was a strong predictor of increased mortality among patients with OSA and it continued to be a significant predictor of mortality even in the non-CAD population. These findings suggest that IFC can predict mortality in patients with OSA even after accounting for CAD. A subgroup of patients with OSA with IFC and abnormal DTS had a higher mortality than those with either factor alone. These patients represent a previously undescribed high-risk group among patients with OSA referred for cardiac stress testing. Our study suggests that the addition of IFC may be able to improve the ability of a stress test to predict mortality in patients with OSA when DTS is normal and may also help identify a group of patients at especially high risk when IFC is found among patients with an abnormal DTS.
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Author Contributions: S.A.N.: concept, data acquisition and interpretation, drafting, revising, final approval; R.M.: concept, data acquisition and interpretation, drafting, final approval; S.D.: data acquisition, revision, final approval; A.V.H.: data analysis and interpretation, revision, final approval; V.K.: data acquisition, interpretation, revision, final approval; W.J.: data acquisition, interpretation, revision, final approval; O.A.M.: concept and design, data acquisition, analysis and interpretation, revision, final approval.
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