The syndrome of angina pectoris with a normal coronary arteriogram, often termed cardiac syndrome X (CSX), is an important clinical entity 1. About 30% of patients with anginal chest pain have normal coronary angiograms. CSX is diagnosed in the presence of typical exercise-induced angina pectoris, transient ischemia-like ST-segment depression during pain, and angiographically normal coronary arteries 2. CSX results from a variety of pathogenic mechanisms. Recently, microvascular coronary dysfunction, a disorder of coronary resistance vessels, has been proposed to be one of the key mechanisms for CSX 3.
Obstructive sleep apnea (OSA) is a common disorder that causes a number of physiologic stressors, including overnight hypoxia and sympathetic nervous system activation 4, which may cause adverse cardiovascular responses. Recent studies have also shown positive associations between OSA and microvascular disease 5. Unfortunately, to the best of our knowledge, previous investigations of associations between OSA and coronary endothelial function are scarce. Therefore, in the present study, we investigated the relationship between OSA and coronary microcirculatory function. To determine whether OSA is associated with impaired coronary endothelial function, we correlated the apnea–hypopnea index (AHI) with coronary endothelial function as determined by the response to intracoronary infusions of ATP.
Patients and methods
We recruited 1038 consecutive patients with chest pain, angiographically normal epicardial coronary arteries, and normal left ventricular function without any regional wall motion abnormalities on two-dimensional echocardiography from the First Affiliated Hospital of Zhengzhou University, the Second Affiliated Hospital of Zhengzhou University, and the Central Hospital of Zhoukou City, and the patients were prospectively enrolled between January 2010 and March 2013. Exclusion criteria included patients with angiographically documented coronary spasm (>50% luminal narrowing) after intracoronary injection of ATP, left ventricular hypertrophy (ECG: Sokolow–Lyon>38 mm; Cornell>2440 mm ms), valvular heart disease (aortic stenosis, aortic regurgitation, bicuspid aortic valve disease, mitral stenosis, mitral regurgitation, mitral valve prolapsed, tricuspid stenosis, tricuspid regurgitation, pulmonic valve disease, multivalvular disease, and so on), or unstable angina. Informed consent was obtained from all participants and the study was approved by the local ethics committee. All patients underwent exercise stress testing, coronary angiography, and biochemical analysis within a period of 1 week. BMI, as a general measure of obesity, was calculated as weight in kg divided by height in m2. Cardiovascular risk factors including hypertension, diabetes, hypercholesterolemia, smoking, obesity, and a family history of cardiovascular disease (myocardial infarction or stroke in a first-degree relative before the age of 60 years), as well as the current medication, were recorded at study entry among all participants. Obesity is generally defined as a BMI of 30 kg/m2 and higher. Hypertension is defined as mean systolic blood pressure more than 140 mmHg, and mean diastolic blood pressure more than 90 mmHg, or a self-report of a physician diagnosis or medication use. Mean blood pressure was composed of up to four readings on two separate occasions. Hypercholesterolemia was defined as a total cholesterol 6.22 mmol/l or more, or a self-report of a physician diagnosis or medication use. Diabetes was defined as a fasting glucose 7.0 mmol/l or more, or a nonfasting glucose 11.1 mmol/l or more, or a self-report of a physician diagnosis or medication use.
Obstructive sleep apnea
Overnight, full attended polysomnography monitoring was performed using an 18-channel PSG recording system (16-Channel Grass-Telefactor Heritage digital sleep system model 15; Astro-Med Inc., West Warwick, Rhode Island, USA) in the sleep laboratories. The sleep stages were monitored by electroencephalography, electrooculography, and electromyography, according to standard criteria 6, and arousals were defined according to the standard criteria of the American Academy of Sleep Medicine 7. Oronasal airflow was measured with a thermistor, thoracoabdominal movements were monitored with a strain gauge, and the oxyhemoglobin saturation in the blood was monitored by pulse oximetry. The respiratory events were scored manually. Apnea was defined as a cessation of airflow lasting for 10 s or more and hypopnea was defined as a decrease in tidal volume (plethysmograph signal) accompanied by a 4% reduction in oxyhemoglobin saturation. The AHI was calculated as the total number of apnea and hypopnea episodes per hour of sleep. The patient was defined as having OSA when the obstructive component was dominant and the AHI was five or more per hour. The severity of OSA was classified according to the criteria of the American Academy of Sleep Medicine 8.
Coronary flow reserve
All antianginal agents had been discontinued at least 48 h before coronary angiography, and the coronary angiographies were performed by a standard percutaneous radial approach. A 7 F guide catheter (Simmons; Cordis Inc., Bridgewater, New Jersey, USA) was introduced into the left main coronary artery. A 0.014-inch Doppler flow guidewire (FloWire; Cardiometrics, Mountain View, California, USA) was advanced through the guide catheter into the middle segment of the left anterior descending coronary artery. After coronary flow velocity at rest was measured, maximal hyperemic flow velocity was induced by intracoronary injection of 50 mg of ATP to determine the coronary flow reserve (CFR) 9. Average peak velocities were measured at baseline and at intracoronary administration of ATP. All patients were in sinus rhythm at the time of study. Measurements were performed in the left anterior descending coronary artery. Mean arterial blood pressure and heart rate were monitored during the study.
Data analysis was carried out using SPSS 16.0 (SPSS Inc., Chicago, Illinois, USA). Results were expressed as mean±SD for numeric variables and number (%) for categorical variables. Multiple groups were compared by analysis of variance for continuous variables, followed by the Bonferroni method for post-hoc analysis. The χ 2-test was used for categorical variables. On the basis of a CFR cutoff value of 2.5 10,11 and considering CFR as a category variable, multivariate logistic regression analysis was performed to examine the association between increasing AHI categories and CFR of 2.5 or less. A two-tailed P-value of less than 0.05 was considered significant.
Table 1 presents the baseline characteristics of the study sample by the severity of OSA, as measured by increasing AHI categories. Patients with higher AHI values had a lower CFR, were more likely to have a higher total cholesterol, low-density lipoprotein cholesterol, and high sensitive C-reactive protein (hsCRP), and were more likely to be obese. Moreover, it was found that the prevalence of OSA was very high in patients with syndrome X (635/1038).
There were no statistically significant differences in the CFR measurements between the mild-to-moderate OSA and the severe OSA groups (P=0.132) (Fig. 1). The CFR was significantly higher in both the moderate OSA and the severe OSA groups compared with the non-OSA patient group (P<0.01) (Fig. 1). In addition, there were no statistically significant differences in the hsCRP measurements between the mild-to-moderate OSA and the severe OSA groups (P=0.247) (Fig. 2). The hsCRP was significantly higher in the severe OSA group (P=0.002) compared with the non-OSA group (Fig. 2).
Table 2 shows the association between increasing AHI categories and CFR in multivariate regression analysis model 1. As compared with having no sleep apnea, we observed that categories with higher AHI were associated with increased odds of lower CFR, after adjustment for age, sex, cardiovascular risk factors (obesity, smokers, hypertension, hypercholesterolemia, low-density lipoprotein cholesterol, diabetes mellitus), and taking drugs. Moreover, they still have negative association in model 2, after adjustment for age, sex, cardiovascular risk factors, heart rate, mean blood pressure, average peak velocity during operation, and taking drugs.
This is the largest study to date evaluating the relationship between OSA and the coronary microcirculatory function. A major finding of the study is that AHI correlates with coronary microcirculatory dysfunction and is a strong and independent predictor of CFR. Moreover, prevalence of OSA is very high in patients with syndrome X.
Atherosclerosis has been suggested to be an inflammatory disease 12 initiated by endothelial dysfunction caused by several risk factors. Recent studies have shown that OSA may be related to microvasculature by the inflammatory mediators 13,14. Various animal and human studies have supported the occurrence of vascular inflammation in OSA. In a rat model, recurrent obstructive apneas led to a significant increase in various leukocyte–endothelial cell interactions such as leukocyte rolling and firm adhesion of leukocytes in comparison with a sham group 15. Vascular inflammation led to increased CRP concentrations, either secondarily or with CRP as a direct participant in the inflammatory process 16, attenuating nitric oxide production in the endothelium 17. In addition, Arnaud et al. 18 showed that T-cell activation, ICAM-1 expression, and leukocyte rolling were associated with early inflammatory vascular remodeling. Fichtlscherer and colleagues 19–21 have shown that the CRP concentration correlates with basal forearm blood flow. Furthermore, Teragawa et al. 22 demonstrated that the increase in coronary blood flow induced by acetylcholine was smaller in patients with increased CRP concentrations. In this study, our findings showed that there was a higher CFR and lower hsCRP from non-OSA to severe OSA groups. These data were in line with previous research and enlarged our scope for the potential role of AHI in patients with coronary microcirculatory dysfunction.
Intermittent hypoxia was also a key feature in the pathophysiology of the coronary microcirculatory dysfunction. Hypoxia-inducible factor-1 was activated in hypoxia, resulting in increased expression of a number of genes encoding proteins such as erythropoietin, vascular endothelial growth factor, and inducible nitric oxide synthase, which increased tissue oxygenation 23,24. At the same time, sustained hypoxia also led to the activation of another critical transcription factor nuclear factor κB 25,26. These factors play a key role in the pathophysiology of the coronary microcirculatory dysfunction.
The aforementioned findings support the hypothesis that higher AHI level confers a higher risk of coronary microcirculatory dysfunction. It is reasonable to believe that a high level of AHI would lower the CFR. To the best of our knowledge, our data obtained in a large group of patients with CSX demonstrate for the first time that OSA is associated with a significant reduction in coronary microcirculatory flow reserve. The main limitation is the cross-sectional nature of the study, which limits our ability to draw conclusions regarding the temporal nature of associations observed. In addition, we did not study the causal relationship between CRP and CFR; therefore, further studies are required to assess whether CRP is directly involved in microcirculatory dysfunction. Moreover, these data were derived from a group of Chinese adults and may differ in other ethnic groups.
Our findings indicate that OSA is associated with coronary microcirculatory dysfunction by the inflammatory mediators. These findings support a close relationship between coronary microcirculatory dysfunction and vascular inflammation in the pathogenesis of atherosclerosis.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
coronary flow reserve; coronary microcirculatory function; inflammation; obstructive sleep apnea