A chronic total occlusion (CTO) is frequently identified in patients undergoing coronary angiography. The prognostic implications of intermittent hypoxia from obstructive sleep apnea (OSA) on patients with a CTO, and effects on collateral recruitment are unknown. The aim of this study was to determine the prevalence, vascular effects, and prognostic implications of the presence of OSA in patients with a CTO. Patients with a CTO between July 2010 and December 2019 were reviewed. Electronic medical records were accessed to determine documented patient history of OSA, demographics, and clinical course. Patients with robust collateral recruitment were defined as Rentrop grade 2 or 3. A total of 948 patients were included in the study, of which 127 (13.4%) had a documented history of OSA. These patients were younger (67.0 years vs 70.6 years, p < 0.01), had a higher body mass index (29.6 kg/m 2 vs 26.7 kg/m 2 , p < 0.0001), higher rates of hypertension (91.3% vs 83.2%, p < 0.05), higher rates of smokers (63.3% vs 49.0%, p < 0.01) and more use of β-blockers (79% vs 68.5%, p < 0.05) and statins (92.7% vs 82.1%, p < 0.01). A documented history of OSA was independently associated with robust collaterals (OR 3.0 95%CI 1.5 to 5.8, p < 0.01) and lower mortality (HR 0.3 95% CI 0.1 to 0.7, p < 0.01) with a mean survival of 10.8 years, as compared to 8.1 years (log rank p < 0.0001). In conclusion, in patients with a CTO, documented OSA is independently associated with more robust coronary collaterals and lower mortality. The possible cardioprotective implications of intermittent hypoxia in OSA, as well as treatment effect requires further investigation.
Highlights
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Obstructive sleep apnea (OSA) causes intermittent hypoxia and thoracic pressure swings.
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OSA is commonly found in patients with a chronic total occlusion (CTO).
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The presence of OSA is associated with more robust coronary collaterals.
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OSA is independently associated with lower mortality in patients with a CTO.
A coronary chronic total occlusion (CTO) is the presence of a completely occluded coronary artery, angiographically appreciated as the presence of collaterals filling the occluded vessel. A CTO is identified in almost 7% of patients presenting with an acute coronary syndrome, and 18% to 52% in patients with stable coronary artery disease (CAD). , The precise etiology and predictors of collateral recruitment and maturation, vital for the development of a CTO, remain uncertain. , However, one of the possible mechanisms by which this may occur is through ischemic preconditioning, whereby brief, intermittent ischemia, renders tissue, tolerant to subsequent ischemia. , Obstructive sleep apnea (OSA) is a chronic, sleep-related breathing disorder characterized by periodic obstruction of the pharyngeal airway during sleep, resulting in repetitive apneas. The prevalence of OSA in CAD is 38% to 65%, significantly greater than in the general population. The hallmarks of OSA, namely intermittent hypoxia and exaggerated intrathoracic pressure swings have acute and chronic effects on hemodynamics and cardiovascular function. Thus, it is plausible that concurrent presence of OSA may be associated with development of, and in turn prognosis in, patients with a CTO. We sought to determine the prevalence and prognostic implications of OSA in patients with a CTO and predictors of collaterals in this population.
Methods
We reviewed all patients undergoing coronary angiography at our tertiary center from July 2010 to December 2019. We identified patients who had a reported CTO in their angiography report through a commercially available reporting system (McKesson, Irving, Texas). Patients who had had a prior coronary artery bypass graft (CABG) were excluded from the analysis to allow characterization of native collaterals alone. Patients presenting with ST elevation myocardial infarction (STEMI), whereby acute recruitment of robust collaterals is associated with improved prognosis, were also excluded to focus on patients with chronically developed collaterals. To ascertain whether patients had a coexistent diagnosis of OSA, electronic medical records and records from the hospital’s sleep investigation laboratory were reviewed to identify a documented history of OSA. Procedural characteristics, in-hospital course along with left ventricular function and biochemical results were reviewed. Left ventricular function was assessed by transthoracic echocardiography, or if not performed, then based on ventriculography at the time of the procedure. The presence and degree of collaterals were graded according to the Rentrop classification, where grade 0 = no filling of any collateral channel; grade 1 = filling of the side branches of the infarct related artery; grade 2 = partial filling of the epicardial vessel of the infarct related artery; grade 3 = complete filling of the epicardial vessel. Patients with Rentrop grade 0 or 1 collaterals were defined as having poor collaterals, whilst those with Rentrop grade 2 or 3 were defined as robust collaterals. Angiographic determination of the collateral connection (CC) grade, which is based on the size of the collaterals, rather than their ability to opacify the epicardial vessel, was also assessed. The donor vessel was defined as the epicardial vessel which provided the predominant collaterals to the occluded vessel. In patients with multiple CTOs, the subsequent angiographic and collateral data (i.e., Rentrop classification) referred to the vessel which corresponded to the greatest ischaemic territory, which in most cases was the left anterior descending (LAD) artery. If no LAD CTO was present, then the vessel which had the more proximal location of the CTO was used.
Emergent indication for coronary angiography was defined as acute coronary syndrome, including unstable angina and non-ST elevation myocardial infarction or ventricular arrhythmia or cardiac arrest not fulfilling criteria for STEMI. Left ventricular impairment was defined as left ventricular ejection fraction (LVEF) ≤50% as determined by echocardiography or ventriculography. Valvular heart disease was defined as moderate or severe mitral or aortic valve disease as determined by echocardiography. CTO percutaneous coronary intervention (PCI) technical success was defined as <30% residual diameter stenosis within the treated segment and restoration of thrombolysis in myocardial infarction (TIMI) grade 3 antegrade flow. Management of the CTO was based upon both intention to treat (including patients who had attempted CTO PCI but was unsuccessful) as well as ‘as treated’ whereby patients’ who had failed CTO PCI were stratified by subsequent management – CABG or medical management. Project approval by the local human ethics committee was obtained prior to data analysis.
Categorical variables were reported as percentages, whilst continuous variables were presented as means (± standard deviation) or as medians and interquartile ranges, depending on distribution of data. Comparisons between groups were performed using Pearson’s chi square test for all categorical variables. Continuous variables were firstly assessed by the Shapiro-Wilk test to ascertain normality of distribution, after which, a student’s T-test was used for normally distributed data, while the Mann-Whitney U test was used for continuous data not distributed normally. Multivariate logistic regression analyses were performed to determine variables associated with the recruitment of robust collaterals. Variables included in the model were those which had a correlation on univariate analysis with robust collateral recruitment, with entry and exit criteria of variables included in the model set at p <0.1. Cox regression analysis was performed to determine the independent predictors of mortality with entry set at p <0.05 and removal at p <0.1 from the model. Both multivariate models were built by forward linear regression. All data were analyzed at the patient level. All tests were 2-sided, and a p <0.05 was considered statistically significant. Analyses were performed using SPSS (version 24, IBM, New York, New York).
Results
A total of 948 patients with a CTO were identified, of which 127 (13.4%) had a documented history of OSA within their medical records, while 821 (86.6%) patients had no documented history of OSA. The mean age was 70.2 years (± 12.3) with 773 (81.5%) males. The indication for angiography was stable angina in 458 (48.3%) with the remaining 490 patients having emergent indications. The CTO vessel was the LAD in 224 (23.6%) patients, the left circumflex artery (LCx) in 197 (20.8%) patients, and the right coronary artery (RCA) in 527 (55.6%) patients. Two hundred and twenty patients (23.2%) had an attempt at CTO percutaneous coronary intervention (PCI), of which 185 (84.1%) achieved technical success. Two hundred and ninety-one patients (30.7%) underwent coronary artery bypass grafting, whilst 472 (48.8%) underwent medical management to the CTO, including PCI to a non-CTO lesion.
Baseline and angiographic differences between patients with documented OSA and those without OSA are summarized in Table 1 . Patients with OSA were younger, had a higher body mass index (BMI), higher rates of hypertension, and higher rates of smokers compared to those without a history of OSA. With respect to medications at the time of angiography, patients with a documented history of OSA were more likely to be prescribed β blockers and statins. Patients with a documented history of OSA also had a significantly higher rate of robust collaterals compared to those without a documented history of OSA. There were no differences in the CCS or management strategies with respect to intention to revascularize the CTO, successful CTO revascularisation, or final management of the CTO ( Table 2 ).
| Variable | Obstructive sleep apnea | p value | |
|---|---|---|---|
| YES n = 127 | NO n = 821 | ||
| Age (years) | 67 (± 14.1) | 70.6 (± 12.0) | <0.01 |
| Men | 108 (85%) | 665 (81%) | 0.27 |
| BMI (kg/m 2 ) | 29.6 (26.2 – 33.6) | 26.7 (24.0 – 29.9) | <0.0001 |
| Hypertension | 116 (91%) | 672 (83%) | <0.05 |
| Hypercholesterolaemia | 111 (87%) | 647 (81%) | 0.07 |
| Smoker | <0.01 | ||
| Never | 44 (37%) | 385 (51%) | |
| Former | 59 (49%) | 260 (34%) | |
| Current | 17 (14%) | 110 (15%) | |
| Diabetes Mellitus | 49 (39%) | 277 (35%) | 0.39 |
| Previous AMI | 49 (39%) | 256 (32%) | 0.12 |
| LVEF (%) | 55 (40 – 55) | 55 (40 – 60) | 0.93 |
| LV Impairment | 59 (48%) | 363 (46%) | 0.76 |
| Valvular Heart Disease | 10 (9%) | 96 (14%) | 0.20 |
| Emergent Indication for angiogram | 58 (46%) | 432 (53%) | 0.14 |
| Number of CTOs | 0.49 | ||
| 1 | 103 (81%) | 677 (82%) | |
| 2 | 21 (16%) | 135 (16%) | |
| 3 | 3 (2%) | 9 (1%) | |
| CTO artery | 0.12 | ||
| Left anterior descending | 26 (20%) | 198 (24%) | |
| Left circumflex | 20 (16%) | 177 (22%) | |
| Right | 81 (64%) | 446 (54%) | |
| CTO of stented vessel | 11 (9%) | 41 (5%) | 0.09 |
| Stenosis in Donor Artery (%) | 50 (30 – 72.5) | 50 (30 – 75) | 0.81 |
| Rentrop | <0.001 | ||
| 0/1 | 11 (9%) | 154 (19%) | |
| 2 | 75 (59%) | 500 (61%) | |
| 3 | 41 (32%) | 167 (20%) | |
| Collateral Connection Score (CCS) | 0.46 | ||
| 0 | 6 (5%) | 55 (7%) | |
| 1 | 27 (21%) | 201 (24%) | |
| 2 | 94 (74%) | 565 (69%) | |
| Medications | |||
| Aspirin | 109 (88%) | 670 (86%) | 0.57 |
| P2Y12 Inhibitor | 78 (63%) | 458 (59%) | 0.39 |
| Beta Blockers | 98 (79%) | 534 (68%) | <0.05 |
| ACE-I/ARB | 76 (61%) | 488 (63%) | 0.77 |
| Nitrates | 30 (24%) | 145 (19%) | 0.14 |
| Statin | 115 (93%) | 640 (82%) | <0.01 |
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