CHEST
Original Research SLEEP DISORDERS
OSA and Coronary Plaque Characteristics Adeline Tan, MBBS; William Hau, PhD; Hee-Hwa Ho, MBBS; Haleh Ghaem Maralani, MSc; Germaine Loo; See-Meng Khoo, MBBS; Bee-Choo Tai, PhD; A. Mark Richards, MD, PhD; Paul Ong, MD; and Chi-Hang Lee, MD
Background: Virtual histology intravascular ultrasound (VH-IVUS) is an intravascular imaging technique that enables the characterization of coronary plaques. We sought to determine the association between OSA and coronary plaque characteristics in patients presenting with coronary artery disease. Methods: We prospectively recruited patients with angiographically proven coronary artery disease for a VH-IVUS examination and home-based sleep study. The total atheroma volume of the entire target coronary artery and the incidence of thin cap fibroatheroma of patients with no to mild and moderate to severe OSA were compared. Results: One hundred eighteen patients were recruited from two university-affiliated centers. Among the 93 patients who completed the study, 32 (34.4%) had newly diagnosed moderate to severe OSA (apnea-hypopnea index . 15). Compared with patients with no to mild OSA, those with moderate to severe OSA had a larger total atheroma volume (461.3 ⫾ 250.4 mm3 vs 299.2 ⫾ 135.6 mm3, P , .001), and the association remained after adjustment for age, BMI, hypertension, diabetes mellitus, smoking, and hyperlipidemia (relative mean difference, 1.73; 95% CI, 1.38-2.15). In contrast, there were no significant differences between the patients with moderate to severe OSA and no to mild OSA regarding the prevalence of thin cap fibroatheroma in the culprit lesion (53.1% vs 54.2%, P 5 .919). Conclusions: In patients presenting with coronary artery disease, moderate to severe OSA was independently associated with a larger total atheroma volume in the target coronary artery. Further studies on the effects of CPAP on total atheroma volume are warranted. Trial registry: ClinicalTrials.gov; No.: NCT01306526; URL: www.clinicaltrials.gov CHEST 2014; 145(2):322–330 Abbreviations: AHI 5 apnea-hypopnea index; IVUS 5 intravascular ultrasound; Spo2 5 oxygen saturation as measured by pulse oximetry; VH-IVUS 5 virtual histology intravascular ultrasound
1.3 million patients present with acute Approximately coronary syndrome annually in the United States, 1
and OSA is increasingly recognized as an independent risk factor for acute coronary syndrome, stroke, and cardiovascular mortality.2,3 OSA is a common condition, with an estimated prevalence in the range of 3% to 7% among the general population and up to 66% in patients with acute coronary syndrome.4,5 Investigations are under way to understand how the diagnosis of OSA can best be integrated into clinical algorithms for cardiovascular risk stratification. Elucidating the effects of OSA on the coronary vasculature is crucial in risk assessments and therapeutic recommendations for affected individuals. Several studies have shown that OSA is independently associated with early mark-
ers of atherosclerosis, with most performed on the carotid and peripheral arteries.6-8 Relatively few studies have evaluated the association between OSA and atherosclerosis in coronary arteries. Coronary atherosclerotic plaque is the fundamental pathologic substrate that underlies the occurrence of ischemic events. Previous studies have shown with coronary angiography and CT imaging a positive association between OSA and coronary artery disease.9-12 However, these nonintravascular imaging modalities provide a relatively crude measurement of the extent of coronary artery disease and preclude the accurate measurement of the total atheroma volume. Moreover, these imaging modalities do not allow the evaluation of the tissue composition of coronary plaque.
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Virtual histology intravascular ultrasound (VH-IVUS) is an intravascular imaging technology that allows the direct assessment of the coronary arteries.13 VH-IVUS, thus, provides a unique insight into the burden and tissue composition of atherosclerotic plaques and allows a comprehensive characterization of the vessel wall. It also demonstrates the ubiquitous presence of plaque in regions that seem normal when assessed by coronary angiography. The total atheroma burden has been shown to be associated with adverse cardiovascular outcomes, and thin cap fibroatheroma, which is defined as a plaque with a large necrotic core abutting the artery lumen, is more prevalent in patients at high risk of acute coronary syndrome.14,15 In this prospective study, we sought to determine the association between OSA and total atheroma volume and thin cap fibroatheroma by VH-IVUS in patients presenting with coronary artery disease.
Materials and Methods Study Design and Patients IDEAS (Intravascular Ultrasound Diagnostic Evaluation of Atherosclerosis in Singapore)-OSA was a prospective study conducted at two university-affiliated centers between February 2011 and December 2012. Patients aged ⱖ 21 years who were undergoing clinically indicated coronary angiography and had been found to have at least one significant (. 50% visual estimation) de novo stenosis in a native coronary artery were eligible. The general exclusion criteria for the study were known OSA based on a previous sleep study, cardiogenic shock (systolic BP , 90 mm Hg), chronic renal failure on dialysis, previous intervention treatment to the target vessel, atrial fibrillation, and inability to provide informed consent. The angiographic exclusion criteria were angiographically visible residual thrombus despite thrombus aspiration or thrombectomy, a heavily calcified lesion, a tortuous vessel, chronic total occlusion, a significant left-sided main lesion, and a distal lesion Manuscript received May 16, 2013; revision accepted October 1, 2013. Affiliations: From the Division of Respiratory Medicine (Drs Tan and Khoo), University Medical Cluster, National University Health System; Department of Medicine (Drs Hau, Richards, and Lee and Ms Loo), Yong Loo Lin School of Medicine, National University of Singapore; Department of Cardiology (Drs Ho and Ong), Tan Tock Seng Hospital; Saw Swee Hock School of Public Health (Ms Ghaem Maralani and Dr Tai), National University of Singapore, National University Health System; and Department of Cardiology (Drs Richards and Lee), National University Heart Centre, Singapore. Dr Tan is currently at Alexandra Hospital (Jurong Health Services) (Singapore). Funding/Support: This study was funded by the Academic Research Fund [Grant R172-000-239-112] of the Ministry of Education, Singapore. Correspondence to: Chi-Hang Lee, MD, Department of Cardiology, National University Heart Centre, Singapore, 1E Kent Ridge Rd, NUHS Tower Block Level 9, Singapore 119228; e-mail:
[email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1163
too small to accommodate an intravascular ultrasound (IVUS) catheter. VH-IVUS examination was performed on the entire target artery of the recruited patients. Daytime sleepiness was assessed with the Epworth Sleepiness Scale. A home-based overnight sleep study was arranged for the recruited patients within 30 days of hospital discharge. The need to abstain from alcohol and hypnotics before the sleep study was highlighted to the patients. The National Healthcare Group Domain Specific Review Board approved the research protocol (reference: C/2010/00341), and informed consent was obtained from the subjects. IVUS Examination A guiding catheter was used to selectively cannulate the ostium of the target coronary artery. Immediately after the guidewire advancement but before balloon predilation, a 20-MHz, 3.5F, phased-array IVUS catheter (Eagle-Eye Gold; Volcano Corporation) was inserted into the mid to distal segment of the target coronary artery. The IVUS catheter was automatically pulled back to the ostium of the guiding catheter using a motorized pullback device at a speed of 0.5 mm/s (R-100 Pullback Device; Volcano Corporation). All images were recorded in digital format on a DVD for subsequent off-line quantitative analysis by two investigators (W. H., C.-H. L.) who were blinded to the sleep study data. Any discrepancies between the analyses of the two investigators were resolved by consensus. IVUS Analyses Conventional gray-scale quantitative IVUS analyses were performed according to the IVUS expert consensus document.16 The following parameters were measured in both the culprit and the nonculprit lesions captured in the target coronary artery (Fig 1): (1) the external elastic membrane area (in square millimeters), (2) the minimal lumen diameter (in millimeters), (3) the minimal lumen area (in square millimeters), and (4) the plaque burden (in square millimeters). The VH-IVUS images were analyzed according to published guidelines.17 The four VH-IVUS plaque components were colorcoded and displayed on the VH-IVUS console, with fibrous tissue shown in green, fibrofatty tissue in light-green, dense calcium in white, and the necrotic core in red. Volumetric measurements using Simpson’s rule were performed over the entire region of interest by tracing the external elastic membrane and lumen border. The volumetric value of each of the four plaque components as well as for the culprit lesion plaque volume and the nonculprit lesion plaque volume were then automatically calculated by VIAS 3.0 (Volcano Corporation) off-line analysis software.17 Total plaque volume of the entire target coronary artery was determined by taking the sum of the culprit lesion and nonculprit lesion plaque volumes. Thin cap fibroatheroma (Fig 2) was defined as a plaque with a . 10% confluent necrotic core, with . 30° of the necrotic
Figure 1. Virtual histology intravascular ultrasound analysis of the culprit lesion and the entire target coronary artery.
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Figure 2. Thin cap fibroatheroma. ILD 5 in-line display; VH-IVUS 5 virtual histology intravascular ultrasound. core abutting the lumen in three or more consecutive frames.18 In a study of . 3,800 VH-IVUS frames, intraclass correlation coefficient was used to compare the plaque constituent area and volumes. It was found that the majority of intraobserver and interobserver measurements had an intraclass correlation coefficient . 0.92, confirming excellent agreement.19 Overnight Sleep Study The sleep studies were performed with a portable diagnostic device (Embletta Gold; Natus Medical Incorporated) that was validated against in-laboratory polysomnography.20 The parameters measured were airflow (nasal cannula and thermistor), respiratory movements (respiratory inductance plethysmography), oxygen saturation as measured by pulse oximetry (Spo2), snoring episodes, ECG, and body position. Outputs from the portable diagnostic device were manually scored by an investigator with no knowledge of the clinical characteristics of the patients (A. T.). The primary measurement of the sleep study was the apnea-hypopnea index (AHI), which was quantified as the total number of apneas and hypopneas per hour of recording time in bed. Apneas were defined as a ⱖ 90% decrease in airflow from baseline for at least 10 s and were further classified as obstructive or central based on the presence or absence, respectively, of respiratory-related chest wall movements. Hypopneas were defined as a 30% to 90% reduction in airflow from baseline lasting 10 s in conjunction with a . 4% desaturation. The oxygen desaturation index was the number of times per hour of recording time in bed that there was a . 4% desaturation. The scoring was performed according to American Academy of Sleep Medicine guidelines.21 We also recorded the following data from the sleep studies: baseline Spo2, lowest Spo2, and time with Spo2 , 90% as a percentage of the total recording time in bed and in minutes. The recruited patients were classified into moderate to severe OSA (AHI . 15) and no to mild OSA (AHI ⱕ 15) groups. Statistical Analysis The relationship between the continuous variables and OSA status was assessed with an independent-sample t test if the data
were normally distributed and a Mann-Whitney U test if skewed. The x2 test was used to evaluate the association between categorical variables and OSA status. Linear regression was used to investigate the relationship between the total atheroma volume and the covariates. Because total atheroma volume (the outcome of interest) had a skewed distribution, its logarithmic form was considered in the model building. We categorized baseline Spo2, lowest Spo2, and total percent time with Spo2 , 90% into quartiles because log transformation did not improve the normality of the data. In examining the association between total atheroma volume and OSA, we further adjusted for the effect of potential confounders (ie, age, BMI, hypertension, diabetes mellitus, smoking, hyperlipidemia) with multiple linear regression. All statistical evaluations were made assuming a two-sided test based on a 5% level of significance. Statistical analyses were performed with Stata 11 (StataCorp LP) software.
Results Baseline Characteristics A total of 141 eligible patients were screened for entry into the IDEAS-OSA study between February 2011 and December 2012. Among the 118 patients recruited, 21 (including one who suffered sudden cardiac death) withdrew and did not complete the sleep study. The remaining 97 patients underwent the sleep study, and 93 successfully completed it (Fig 3). The sleep study and VH-IVUS data of these 93 patients were reviewed and analyzed as defined. The mean BMI of the patients was 25.6 ⫾ 4.1 kg/m2. The prevalence of being overweight (BMI, 25-30 kg/m2) and obese (BMI . 30 kg/m2) was 34.4% and 12.8%, respectively. Based on an Epworth Sleepiness Scale score of , 10, 65 patients (70%) were nonsleepy. The demographic and clinical characteristics of the patients are shown in Table 1. About
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Original Research
inhibitors (72.0%) was high and similar between the moderate to severe OSA and no to mild OSA groups (data not shown). At 30-day follow-up, stent thrombosis developed in one patient from the no to mild OSA group. Overnight Sleep Study
Figure 3. Study flowchart. See Figure 2 legend for expansion of abbreviation.
30% of the recruited patients had diabetes mellitus, but none had undergone previous coronary artery bypass graft surgery. The most common clinical presentations were ST-elevation myocardial infarction and non-ST-elevation myocardial infarction. Coronary angiography was performed urgently in patients who presented with ST-elevation myocardial infarction and electively in all remaining patients. On hospital discharge, all recruited patients were treated with antiplatelet agents and statin therapy. The use of b-blockers (89.2%) and angiotensin-converting enzyme
The median duration between the VH-IVUS examination and the overnight sleep study was 12 days (interquartile range, 6-23 days). The mean and median levels of the AHI were 13.6 and 9.3, respectively. Based on an AHI . 15, moderate to severe OSA was newly diagnosed in 32 patients (34.4%). The patients with moderate to severe OSA were older, had a higher BMI and prevalence of hypertension, and were less likely to be smokers. The sleep study results of the patients in the moderate to severe OSA and no to mild OSA groups are shown in Table 2. The Epworth Sleepiness Scale score for the 93 study patients was 8.2 ⫾ 4.3, and there was a strong trend toward a higher score for those with moderate to severe OSA (P 5 .058). Total Atheroma Volume The quantitative VH-IVUS analysis findings are shown in Table 3. There were no significant differences between the moderate to severe OSA and no to mild OSA groups regarding the culprit lesion atheroma volume, whether this was assessed at the minimal
Table 1—Patient Demographics and Clinical Characteristics Characteristic Age, y Male sex BMI, kg/m2 Cardiovascular risk factors Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history of coronary artery disease Concomitant conditions Previous myocardial infarction Previous percutaneous coronary intervention Chronic renal failure Previous stroke Ethnicity Chinese Malay Indian Other Clinical presentations ST-elevation myocardial infarction Non-ST-elevation myocardial infarction Unstable angina Stable angina
Overall (N 5 93)
Moderate to Severe OSA (n 5 32)
No to Mild OSA (n 5 61)
P Value
54.4 ⫾ 8.6 81 (87.1) 25.6 ⫾ 4.1
57.5 ⫾ 6.9 26 (81.2) 26.8 ⫾ 4.2
52.8 ⫾ 9.0 55 (90.2) 24.9 ⫾ 3.9
.011 .223 .028
42 (45.2) 48 (51.6) 24 (25.8) 75 (80.7) 29 (31.2)
6 (18.7) 23 (71.9) 11 (34.4) 29 (90.6) 8 (25.0)
36 (59.0) 25 (41.0) 13 (21.3) 46 (75.4) 21 (34.4)
, .001 .005 .171 .078 .351
18 (19.3) 19 (20.4) 2 (2.1) 3 (3.2)
8 (25.0) 7 (21.9) 2 (6.2) 1 (3.1)
10 (16.4) 12 (19.7) 0 (0.0) 2 (3.3)
.318 .802 .116 1.000
60 (64.5) 16 (17.2) 14 (15.0) 3 (3.2)
21 (65.6) 7 (21.9) 4 (12.5) 0 (0.0)
39 (63.9) 9 (14.7) 10 (16.4) 3 (4.9)
.491 … … …
39 (41.9) 29 (31.2) 3 (3.2) 22 (23.7)
9 (28.1) 14 (43.7) 2 (6.2) 7 (21.9)
30 (49.2) 15 (24.6) 1 (1.6) 15 (24.6)
.097 … … …
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Table 2—Sleep Study Findings of the Recruited Patients Characteristic
Overall (N 5 93)
Moderate to Severe OSA (n 5 32)
No to Mild OSA (n 5 61)
P Value
Duration from VH-IVUS to sleep study, d Baseline Spo2, % Lowest Spo2, % Total time with Spo2 , 90%, % Time Spo2 , 90%, min ODI, /h Epworth Sleepiness Scale score
12 (6-23) 95.2 ⫾ 1.5 84.7 ⫾ 6.9 2.3 ⫾ 5.2 0.6 (0-8.7) 10.2 (3.6-20.7) 8.2 ⫾ 4.3
12 (6-19.5) 94.5 ⫾ 1.6 79.9 ⫾ 7.6 4.8 ⫾ 7.5 9.9 (1.6-23.2) 27.3 (20.5-34.0) 9.4 ⫾ 3.6
13 (6-26) 95.6 ⫾ 1.4 87.2 ⫾ 4.9 1.0 ⫾ 2.8 0.2 (0-1.8) 5.8 (2.4-10.7) 7.6 ⫾ 4.5
.662 , .001 , .001 , .001 , .001 , .001 .058
Data are presented as median (interquartile range) or mean ⫾ SD. ODI 5 oxygen desaturation index; Spo2 5 oxygen saturation as measured by pulse oximetry; VH-IVUS 5 virtual histology intravascular ultrasound.
moderate to severe OSA and no to mild OSA groups. For the entire target coronary artery, most patients had either no or one thin cap fibroatheroma, and there was no significant difference between the moderate to severe OSA and no to mild OSA groups regarding the total number of thin cap fibroatheromas (Table 5).
lumen area site (plaque burden) or for the entire culprit lesion. However, the total atheroma volume of the entire target coronary artery was significantly higher in the patients with moderate to severe OSA than in those with no to mild OSA (Fig 4). The univariate analysis of the total atheroma burden is shown in Table 4. Moderate to severe OSA, total percentage of time with an oxygen saturation of , 90%, age, and smoking were associated with total atheroma volume. After adjustment for age, BMI, hypertension, diabetes mellitus, smoking, and hyperlipidemia, moderate to severe OSA remained an important predictor of total atheroma volume (relative mean difference, 1.73; 95% CI, 1.38-2.15; P , .001).
Discussion We prospectively recruited patients presenting with coronary artery disease for a VH-IVUS examination and home-based sleep study. The main findings of the study are that 34.4% of the patients had newly diagnosed moderate to severe OSA. Compared with no to mild OSA, moderate to severe OSA was associated with a larger total atheroma volume in the entire target coronary artery. This association remained significant even after adjustment for confounders, including age, BMI, hypertension, diabetes mellitus, smoking, and hyperlipidemia. In contrast, there were no significant differences between the moderate to severe OSA and no to mild OSA groups regarding the prevalence of thin cap fibroatheroma.
Thin Cap Fibroatheroma There were no significant differences between the moderate to severe OSA and no to mild OSA groups in terms of the tissue composition of the plaques, whether this was assessed at the minimal lumen area site or for the entire culprit lesion. Approximately onehalf of the culprit lesions were thin cap fibroatheromas, with no difference seen in lesion type between the
Table 3—Atheroma Volume in Culprit Lesion and Entire Target Coronary Artery Characteristic Culprit lesion External elastic membrane, mm2 Minimal lumen area, mm2 Minimal lumen diameter, mm Plaque burden, mm2 Atheroma volume, mm3 Remodeling index Entire target coronary artery Target coronary artery Left anterior descending artery Left circumflex artery Right coronary artery Total No. lesions in target coronary artery 1 2 ⱖ3 Total atheroma volume, mm3
Overall (N 5 93)
Moderate to Severe OSA (n 5 32)
15.7 ⫾ 6.3 3.6 ⫾ 2.3 1.9 ⫾ 0.5 49.8 ⫾ 28.6 244.2 ⫾ 159.4 1.1 ⫾ 0.2
15.9 ⫾ 5.9 3.6 ⫾ 2.3 1.9 ⫾ 0.5 49.2 ⫾ 24.8 236.5 ⫾ 185.3 1.1 ⫾ 0.3
No to Mild OSA (n 5 61) 15.7 ⫾ 6.5 3.5 ⫾ 2.5 1.9 ⫾ 0.5 50.1 ⫾ 30.6 248.5 ⫾ 144.8 1.0 ⫾ 0.2
P Value .896 .843 .886 .883 .736 .600 .382
57 (61.3) 12 (12.9) 24 (25.8)
17 (53.1) 6 (18.7) 9 (28.1)
40 (65.6) 6 (9.8) 15 (24.6) .783
42 (46.1) 32 (35.2) 17 (18.7) 352.4 (235.7-464.1)
15 (46.9) 10 (31.2) 7 (21.9) 486.3 (393.3-667.2)
27 (45.8) 22 (37.3) 10 (16.9) 279.5 (189.1-375.9)
, .001
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Figure 4. Total atheroma volume in patients with moderate to severe OSA and no to mild OSA.
Coronary artery disease is an important cause of mortality and morbidity worldwide. In both the American Heart Association/American College of Cardiology and the European Society of Cardiology guidelines, OSA is highlighted as a potential risk factor for cardiovascular diseases.22,23 However, despite the ample epidemiologic evidence linking OSA with adverse cardiovascular outcomes, there is a paucity of data on the relationship between OSA and the coronary atherosclerotic process. A previous study reported that Table 4—Univariate Analysis for Total Atheroma Volume Variable OSA (AHI . 15) Baseline Spo2 . 96.3 . 95.5-96.3 . 94.3-95.5 , 94.3 Lowest Spo2 . 89 . 86-89 . 82-86 , 82 Total time with Spo2 , 90%, % 0 . 0-0.2 . 0.2-2.1 . 2.1 Age Male sex BMI Hypertension Diabetes mellitus Smoking Hyperlipidemia
Relative Mean Difference (95% CI) 1.79 (1.48-2.16) Reference 1.16 (0.84-1.58) 1.27 (0.92-1.73) 1.47 (1.07-2.02) Reference 1.08 (0.80-1.46) 1.28 (0.95-1.73) 1.41 (1.06-1.87) Reference 1.14 (0.83-1.58) 1.42 (1.08-1.87) 1.35 (1.03-1.76) 1.02 (1.01-1.03) 0.94 (0.68-1.31) 1.01 (0.99-1.04) 1.19 (0.97-1.48) 1.16 (0.90-1.48) 0.80 (0.65-0.99) 1.17 (0.90-1.54)
P Value , .001 .101 .363 .141 .017 … .082 .621 .107 .019 … .045 .421 .012 .029 … .012 .708 .296 .101 .242 .037 .232
The outcome total atheroma volume was log transformed. AHI 5 apnea-hypopnea index. See Table 2 legend for expansion of other abbreviation.
among 34 patients with chronic total coronary occlusion, those with OSA had better collateral vessel formation.24 In addition, a recent study suggested that OSA is associated with a smaller size of myocardial injury in patients presenting with nonfatal myocardial infarction.25 These important studies highlight the possible effects of intermittent hypoxemia on coronary atherosclerosis process. The primary purpose of the present study was to provide an in vivo confirmation of the hypothesis that OSA affects the total atheroma volume independent of the effects of obesity and traditional cardiovascular risk factors. Although the actual histologic assessment of the coronary arteries in vivo is not feasible, the development of radiofrequency IVUS makes it possible to characterize the vessel wall with an imaging technique that has been shown to correlate reasonably well with histologic findings.13 VH-IVUS enables high-resolution (100-150 mm) imaging of the coronary artery wall. Thin cap fibroatheromas (plaques with a large necrotic core and a thin fibrous cap) seen with VH-IVUS have been shown to be associated with acute coronary syndrome and adverse cardiovascular events.14,15 Despite a high level of interest in the relationship between OSA and coronary artery disease, few data have been compiled from coronary imaging. The previously reported studies in this area have important shortcomings. The use of nonintravascular imaging techniques, a small sample size, and a long and widely varying duration between the sleep study and coronary imaging preclude definite conclusions.9-12 For instance, a recent retrospective study suggested an association between OSA and noncalcified coronary plaques,9 yet the CT scan was performed up to 3 years after the sleep study. It has been demonstrated that the tissue composition of coronary plaques evolves substantially over such long periods.26 In the present study, the total atheroma volume of the target coronary artery was 50% higher in the moderate to severe OSA group than in the no to mild OSA group. This finding is in-line with a previous study in 19 patients that used gray-scale IVUS to show that patients with OSA have a larger coronary atherosclerotic plaque volume.27 This important finding supports the negative prognostic impact of OSA on clinical outcomes in patients with coronary artery disease. A multicenter IVUS study of . 4,000 patients identified a direct relationship between the burden of coronary atherosclerosis and major adverse cardiovascular outcomes.14 Total atheroma volume is a reflection of the atherosclerotic burden and supports the hypothesis that atherosclerosis is an intermediate mechanism that links moderate to severe OSA with increased cardiovascular events. We did not find an association between moderate to severe OSA and plaque vulnerability based on the
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Table 5—Tissue Composition and Prevalence of Thin Cap Fibroatheroma Characteristic Culprit lesion tissue composition at minimal lumen area Fibrous, mm2 Fibrofatty, mm2 Necrotic core, mm2 Dense calcium, mm2 Culprit lesion tissue composition Fibrous, mm3 Fibrofatty, mm3 Necrotic core, mm3 Dense calcium, mm3 Culprit lesion thin cap fibroatheroma Total No. thin cap fibroatheroma in entire target coronary artery 0 1 ⱖ2
Overall (N 5 93)
Moderate to Severe OSA (n 5 32)
No to Mild OSA (n 5 61)
P Value
5.2 ⫾ 3.2 1.2 ⫾ 1.2 2.1 ⫾ 1.3 0.9 ⫾ 2.7
5.0 ⫾ 2.5 1.1 ⫾ 0.9 2.3 ⫾ 1.4 1.6 ⫾ 4.5
5.4 ⫾ 3.5 1.3 ⫾ 1.4 2.0 ⫾ 1.3 0.5 ⫾ 0.4
.572 .519 .394 .062
57.7 ⫾ 32.4 22.8 ⫾ 24.8 42.8 ⫾ 41.3 14.4 ⫾ 14.7 49 (53.8)
64.1 ⫾ 32.5 30.6 ⫾ 35.2 49.0 ⫾ 48.7 15.4 ⫾ 12.6 17 (53.1)
54.4 ⫾ 32.2 18.6 ⫾ 15.4 39.4 ⫾ 36.7 13.8 ⫾ 15.8 32 (54.2)
.174 .027 .296 .624 .919
36 (39.6) 38 (41.8) 17 (18.7)
13 (40.6) 15 (46.9) 4 (12.5)
23 (39.0) 23 (39.0) 13 (22.0)
.513
Data are presented as mean ⫾ SD or No. (%).
prevalence of thin cap fibroatheroma in the study patients. It is possible that the tissue composition of the plaques may have been altered by cardiovascular medication. For instance, statins have been shown to reduce the necrotic core content of coronary plaques and, hence, the incidence of thin cap fibroatheroma.28 Except for patients with ST-elevation myocardial infarction in whom emergency coronary angiography had been performed before the administration of statins, all patients had already been treated with and were, thus, subject to the effects of statins before recruitment. The effects of OSA on the prevalence of thin cap fibroatheroma in coronary plaques may also differ between early and advanced atherosclerosis. The patients in the present study had advanced coronary artery disease according to the high prevalence of cardiovascular risk factors, clinical presentation (70% ST- or non-ST-elevation myocardial infarction), and angiographic findings (all had at least one . 50% coronary stenosis). We acknowledge that the effect of OSA on tissue composition may be more pronounced in asymptomatic patients with early atherosclerosis or an absence of traditional cardiovascular risk factors. However, the invasive nature of VH-IVUS29 precludes the recruitment of such a patient cohort. A major strength of the present study is the performance of a home-based sleep study after hospital discharge rather than an in-hospital sleep study. Although still a controversial area, there is emerging evidence that OSA detected during acute cardiac conditions may be a transient phenomenon.30,31 Ischemia-driven myocardial stunning and dysfunction can lead to water retention, resulting in nocturnal fluid shifts and upper airway narrowing.32 Moreover, sedation and analgesics given to patients presenting with acute myocardial infarction may lead to a loss of pharyngeal dilator
muscle tone and upper airway collapse during sleep. A recent study showed that in patients presenting with acute coronary syndrome and given a diagnosis of OSA during hospitalization, a repeat sleep study at the 6-month follow-up revealed that OSA had resolved in most patients.31 Conducting the sleep study after hospital discharge, thus, ensured that the study patients were clinically stable at the time of the study. The findings detailed in this article must be interpreted in the context of the study’s limitations. After providing informed consent in the hospital, 21 of the 118 recruited patients did not complete the sleep study, with most withdrawing because of hesitancy or reluctance to allow a sleep technician to enter their home to set up the portable sleep device. Although in-laboratory polysomnography is the gold standard in the diagnosis of OSA, the accessibility of in-laboratory polysomnography is very limited in Singapore, and the test usually is applied only to clinical patients. Portable sleep studies conducted in the home setting are an inexpensive and convenient way to circumvent this problem. Indeed, portable sleep study is the method used in many large-scale clinical studies.33 It has been shown that home-based sleep studies provide diagnostic and treatment results equivalent to in-laboratory sleep studies and are covered by health insurance in the United States when used in the diagnosis of OSA.34,35 A further limitation is that the study was conducted in a multiethnic Asian country. There is evidence that the mechanism of OSA may differ between Asians and whites.36 OSA in Asians is mainly due to craniofacial skeletal restriction, whereas in whites, it is more related to obesity.36 Although there is no epidemiologic evidence that the downstream cardiovascular effects of OSA are different in Asians, it is possible that OSA interacts with obesity or other cardiovascular risk factors
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Original Research
differently in the two populations. Thus, it remains unknown whether the results of this study can be extrapolated to whites. In conclusion, we found that moderate to severe OSA is associated with an increased total atheroma volume in patients presenting with coronary artery disease. This association remains significant even after adjusting for cardiovascular risk factors such as BMI, diabetes mellitus, and hypertension. The findings suggest that moderate to severe OSA is an independent risk factor for coronary atherosclerosis in patients with coronary artery disease. Further studies to elucidate the treatment effect of CPAP on the progression of coronary plaques are warranted. Acknowledgments Authors contributions: Dr Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Tan: contributed to the study concept and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Dr Hau: contributed to the study concept and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Dr Ho: contributed to the study concept and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Ms Ghaem Maralani: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Ms Loo: contributed to the drafting of the manuscript and review of the manuscript for important intellectual content. Dr Khoo: contributed to the drafting of the manuscript and review of the manuscript for important intellectual content. Dr Tai: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Dr Richards: contributed to the study concept and design, drafting of the manuscript, and review of the manuscript for important intellectual content. Dr Ong: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Dr Lee: contributed to the study concept and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The authors thank Agnes Chow, Avatton Medical, for assistance with the home-based sleep study; Pei-Ee Lee and Venesa Loh with the patient recruitment; and the sleep laboratory at the National University Hospital, Singapore, for the analysis of the sleep tracings.
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