516 Original research
Cardiac structure and function improvements in coronary artery disease combined with severe obstructive sleep apnea/hypopnea syndrome patients via noninvasive positive pressure ventilation therapy Xinbing Liua, Liuliu Fenga, Guoliang Caob, Hongman Huanga, Qitan Xua, Jianhua Yua, Shufu Zhanga and Mingcheng Zhouc Objective The aim of this study was to investigate the effects of a noninvasive positive pressure ventilation therapy on cardiac structure and function in patients with coronary heart disease combined with obstructive sleep apnea/hypopnea syndrome (OSAHS). Patients and methods Eighty patients with coronary heart disease OSAHS were divided randomly into treatment (n = 40) and control (n = 40) groups. Both groups received standard medications. The treatment group received additional noninvasive mechanical ventilation support for at least 3 h (3–6 h) every night. On the first day after selection and 3 months afterwards, participants were examined with echocardiograms, 24-h ambulatory blood pressure monitoring, and blood analyses. Primary endpoints were left ventricular end-diastolic diameter, left ventricular endsystolic diameter, left ventricular ejection fraction, left atrial diameter as well as serum concentrations of N-terminal prohormone of brain natriuretic peptide, and high-sensitive C-reactive protein. Secondary endpoints included cardiac death, nonfatal myocardial infarction, and hospitalization. Results After the 3-month study period, patients in the treatment group showed significantly improved left ventricular end-diastolic diameter (P = 0.02), left ventricular end-systolic diameter (P = 0.035), left ventricular ejection
Introduction Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a condition characterized by recurrent sleep apnea and hypopnea, and is categorized as a sleep disorder. OSAHS can cause damage to multiple organs, especially the cardiovascular system, leading to deterioration in cardiac structures and function [1,2], and 56% of OSAHS patients show abnormal left ventricular filling patterns often accompanied by higher left ventricular volume and a thickening of the septum and the left ventricular posterior wall. The incidence of heart failure is 2.38 times greater in OSAHS patients than in the nonaffected population, markedly impacting the life expectancy and quality of life of these patients [3,4]. Noninvasive mechanical ventilation is mainly used in patients with chronic obstructive pulmonary disease, neuromuscular disorders, and obstructive sleep apnea (OSA) [5]. During this procedure, the ventilator provides synchronized 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
fraction (P = 0.05), and left atrial diameter (P = 0.02) values, and their serum N-terminal prohormone of brain natriuretic peptide (P = 0.01) and high-sensitive C-reactive protein (P = 0.04) concentrations were significantly improved compared with the control group. During the 3 months, three cardiovascular complications occurred in the treatment group versus nine in the control group (P < 0.05). Conclusion For patients with coronary heart disease combined with OSAHS, noninvasive mechanical ventilation therapy can significantly improve heart functions and reduce the occurrence of cardiovascular complications. Coron Artery Dis 25:516–520 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:516–520 Keywords: cardiac structure and function, continuous positive pressure noninvasive mechanical ventilation, obstructive sleep apnea/hypopnea syndrome, stable coronary artery disease a
Department of Cardiology, Shanghai Shi Dong Hospital, bDepartment of Geriatrics, Shanghai No. 3 People’s Hospital and cDepartment of Cardiology, An Tu Hospital, Shanghai, China Correspondence to Mingcheng Zhou, MD, Department of Cardiology, An Tu Hospital, No. 200 Yanji East Road, Shanghai 200093, China Tel/fax: + 86 21 65489845; e-mail: [email protected] Received 17 February 2014 Revised 18 April 2014 Accepted 29 April 2014
positive airway pressure when patients inhale, which can effectively help overcome airway resistance and reduce the amount of work done by the patient for breathing, thereby effectively improving their respiratory function. When patients exhale, the ventilator can provide a lower positive pressure, reducing or offsetting the patient’s workload, which can effectively reduce fatigue. The current clinical practice in China for the treatment of OSAHS patients with coronary heart disease is still only medication. We hypothesized that for patients with coronary heart disease combined with OSAHS, a noninvasive mechanical ventilation therapy, otherwise used in China only for chronic obstructive pulmonary disease treatment, may have a beneficial impact on cardiac structure and function as an added measure combined with common medications. In this prospective study, we investigated whether or not adding a noninvasive mechanical ventilation therapy to the standard drug DOI: 10.1097/MCA.0000000000000129
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Noninvasive pressure ventilation for OSAHS Liu et al. 517
treatment for stable coronary artery disease combined with OSAHS patients could improve their outcome.
Patients and methods Definition of apnea
Apnea is defined as an interruption to normal airflow of at least 10 s. Hypopnea is diagnosed when one or both of the following conditions are fulfilled: (a) decreased airflow of at least 30% and decreased oxygen saturation of at least 4% compared with baseline levels for at least 10 s; (b) decreased airflow of at least 50% and decreased oxygen saturation of at least 3% compared with the baseline for at least 10 s, or sudden awakening. The severity of sleep apnea is usually determined by the apnea–hypopnea index (AHI), which is the sum of the average number of episodes of apnea and hypopnea per hour of recorded sleep. Mild sleep apnea refers to patients with an AHI of 5–15 times/h of sleep, moderate sleep apnea refers to patients with an AHI of 15–30 times/h of sleep, and severe sleep apnea refers to patients with an AHI greater than 30 times/h of sleep [6]. Patients
All patients in this study, including inpatients and outpatients, were hospitalized in one of three Shanghai hospitals between March 2010 and March 2013 (Shanghai East Hospital, Shanghai An Tu Hospital’s Department of Cardiology, and Shanghai No. 3 People’s Hospital’s geriatric clinics). Inclusion criteria were as follows: (a) male and female patients of any ethnicity between the age of 40 and 75 years; (b) confirmed coronary artery disease including at least one of the following criteria: myocardial infarction in the past (≥90 days before signing the informed consent), coronary angiography showing a 50% or more stenosis in at least one major coronary artery, 64-slice or more spiral computed tomography (Light Speed VCT, Forchheim, Germany) showing 50% or more stenosis in at least one major coronary artery, at least one blood vessel received by percutaneous transluminal coronary angioplasty and/or a percutaneous coronary intervention (≥90 days before signing of informed consent) as well as multiple blood vessels received by coronary artery bypass graft therapy (≥1 year before signing of informed consent); and (c) patients had moderate to severe OSA with an AHI of greater than 15 times/h of sleep, with overnight monitoring showing that oxygen saturation decreased by at least 4% of at least 12 times/h and measured resting awake oxygen saturation of at least 90%. Patients were excluded if they fulfilled any of the following criteria: (a) the doctor or researcher responsible believed that the patient should not participate in the study for any reason, such as severe disability, death likely within the next 2 years, significant memory, perceptual, or behavioral disorders, neurological defects (such as limb paralysis) impeding independent use of the continuous positive airway pressure (CPAP) mask, any planned coronary or peripheral revascularization within
the next 3 months, New York Heart Association heart failure classification class IV, stroke caused by subarachnoid hemorrhage, or previous use of CPAP to treat OSA. Of 110 patients who were screened, 91 patients fulfilled the inclusion criteria; however, six patients declined to sign an informed consent form and were therefore excluded. The remaining 85 patients were divided randomly into either the treatment or the control group. During the course, however, two patients in the treatment group could not tolerate the ventilator therapy plus one patient could not adhere to the required 3 h of use per night. In the control group, one patient purchased a ventilator and used it privately and one patient was lost because of moving. Thus, for the statistical analyses, the treatment group (n = 40) and a control group (n = 40) were included. This study was approved by the Shanghai East Hospital Ethics Committee and each participant signed informed consent. Treatments
The medications for all patients are listed in Table 1. Use of ventilator: all treatment group patients were provided noninvasive ventilator support (S9 Autoset; ResMed, Sydney, New South Wales, Australia) with appropriate masks (Full Face Mirage Quattro masks; ResMed) using the CPAP method, with a respiratory frequency of Comparison of basic data between the treatment group and the control group
Table 1
Items
Treatment group (n = 40)
Age (years) 62.86 ± 9.0 Males 30 (75.0) Hypertension 35 (87.5) Type 2 diabetes 10 (25) 2 BMI (kg/m ) 25.0 ± 4.5 NYHA heart function classification Class I 15 (37.5) Class II 18 (45.0) Class III 7 (17.5) Daytime mean blood pressure (mmHg) Systolic pressure 128.5 ± 11.5 Diastolic pressure 83.5 ± 7.5 Nocturnal mean blood pressure (mmHg) Systolic pressure 131.5 ± 12.5 Diastolic pressure 85.5 ± 7.7 hsCRP (mg/l) 12.20 ± 3.5 Prior medical history Smoking 12 (30.0) Myocardial 5 (12.5) infarction PCI 10 (25.0) CABG 0 (0) Stroke 3 (7.5) Drug treatment ACEI or ARB 30 (75.0) Statins 34 (85.0) Aspirin 38 (95.0) β-Blockers 31 (77.5)
Control group (n = 40)
P-value
63.14 ± 9.1 28 (70.0) 36 (90.0) 12 (30.0) 25.5 ± 4.0
0.476 0.198 0.860 0.428 0.745
13 (32.5) 19 (47.5) 8 (20.0)
0.350 0.618 0.339
127.8 ± 12.0 82.9 ± 7.6
0.830 0.745
130.9 ± 12.6 84.8 ± 7.8 12.04 ± 3.4
0.910 0.890 0.856
10 (25.0) 4 (10.0)
0.096 0.780
8 (20.0) 0 (0) 2 (5.0)
0.180 1 0.890
28 36 36 33
(70.0) (90.0) (90.0) (82.5)
0.578 0.610 0.650 0.680
Values are represented as x ± SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; hsCRP, high-sensitive C-reactive protein; NYHA, New York Heart Association; PCI, percutaneous coronary intervention.
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518 Coronary Artery Disease 2014, Vol 25 No 6
12–16 breaths/min and a pressure of 6–12 cmH2O. The instrument setting was adjusted to achieve sleep time snoring and airflow reduction of 95% and AHI of less than 5 times/h of sleep by ventilation monitoring. Outcome measurements
Primary endpoints were left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVESd), left ventricular ejection fraction (LVEF), left atrial diameter and serum concentrations of N-terminal prohormone of brain natriuretic peptide (NTProBNP), a biomarker for congestive heart failure, as well as high sensitive C-reactive protein (hsCRP) as an indicator for cardiovascular disease progression. A SONOS 7500 cardiac ultrasound machine (Philips, Washington, USA) was used for cardiac structure examination. Peripheral blood (3 ml) was collected from the patients’ median cubital vein, mixed with a disodium edetate (EDTA) solution containing aprotinin in an anticoagulant tube, and centrifuged at 3000 rpm for 15 min within 12 h of collection. The serum was separated and stored at − 70°C until use to avoid repeated freeze–thaw cycles. Serum NT-ProBNP levels were detected using an enzyme-linked immunosorbent assay kit (Roche, Shanghai, China) and hsCRP was determined using a latex-enhanced nephelometry kit (Siemens Ltd). In addition, 24-h ambulatory blood pressure monitoring was performed using an ambulatory blood pressure monitoring instrument and an APN portable sleep monitoring device (ResMed) was used for sleep monitoring. The ventilators used were ResMed Autoset-T automatic pressure-regulating ventilators (ResMed). All patients were monitored on day 1 and after 3 months of noninvasive mechanical ventilation. Secondary endpoints were cardiac death, nonfatal myocardial infarction, and hospitalization. Statistical analyses
SPSS 16.0 statistical analysis software (SPSS Inc., Chicago, Illinois, USA) was used for all analyses. Quantitative data are shown as mean ± SD (x ± SD). Group t-tests were used for baseline comparisons between treatment and control groups and normally distributed data. Two-sample rank tests and Mann–Whitney U-tests were used for non-normally distributed data. Percentages between the two groups were compared using χ2-test or precise probability test. Pretherapy and follow-up data between groups were compared using analysis of variance. A P-value of less than 0.05 was considered statistically significant.
Results Changes in cardiac structure and function during treatment
Forty patients from the treatment group were included in the analysis, 30 men and 10 women, mean age of 62.86 ± 9.0 years; the 40 patients in the control group
included 28 men and 12 women, mean age of 63.14 ± 9.1 years. Comparison of the basic characteristics between the treatment group and the control group showed no statistically significant differences (Table 1). Comparisons between patients in the treatment group and patients in the control group showed that LVEDd (P = 0.02) and LVESd (P = 0.035) were significantly better in the treatment group, indicating a beneficial change of the cardiac structure. In addition, patients in the treatment group receiving noninvasive mechanical ventilation showed a statistically significant improvement in LVEF (P = 0.05), indicating that they achieved superior heart function improvement. The left atrial diameter was also significantly reduced in the treatment group compared with the control group (P = 0.02; Table 2). Biomarker changes during treatment
Serum NT-ProBNP concentrations in the treatment group were 586.5 ± 67.8 pg/ml at day 1 and 385.4 ± 42.5 pg/ml after 3 months and in the control group they were 578.4 ± 67.0 pg/ml at day 1 and 560.0 ± 68.1 pg/ml after 3 months. The treatment group experienced a greater reduction and the difference compared with the change in the control group was statistically significant (P = 0.001). The hsCRP serum concentrations in the treatment group were 12.20 ± 3.5 mg/l at day 1 and 5.7 ± 1.5 mg/l after 3 months and those in the control group were 12.24 ± 3.4 mg/l at day 1 and 12.11 ± 3.6 mg/l after 3 months. The reduction in the treatment group was significantly better than that in the control patients (P = 0.04; Table 2). Changes in ambulatory blood pressure before and after treatment
On comparing the daytime mean blood pressures between the two groups, only the diastolic pressure decreased significantly more in the treatment group compared with the control group (P = 0.04). Both the nocturnal mean diastolic (P = 0.01) and the systolic (P = 0.002) pressures, however, were reduced in the treatment group to a significantly higher extent compared with the control patients. Secondary endpoint events
During the 3 months of the study, there were a total of 12 complications in the two groups; three occurred in the treatment group (3/43) and nine in the control group (9/42), and the difference was statistically significant (Table 3). The reasons for hospitalization were cardiac events including acute coronary syndrome, heart failure, and cardiac embolism, accompanied by severe arrhythmia symptoms.
Discussion OSAHS can induce changes in cardiac structure and function through a variety of factors: enhanced
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Noninvasive pressure ventilation for OSAHS Liu et al. 519
Table 2
Comparison of the treatment group and the control group data at day 1 and after 3 months Treatment group (n = 40)
AHI mSaO2 LVEDd (mm) LVESd (mm) LVEF ProBNP (pg/ml) hsCRP (mg/l) Daytime mean blood pressure Systolic Diastolic Nocturnal mean blood pressure Systolic Diastolic Left atrial diameter (mm)
Control group (n = 40)
Day 1
3 months
Change
Day 1
3 months
Change
P-value
30.2 ± 10.2 79.2 ± 9.6 49.6 ± 6.7 37.6 ± 5.0 0.50 ± 0.11 586.5 ± 67.8 12.20 ± 3.5
3.2 ± 2.6 92.2 ± 7.2 45.6 ± 5.9 35.4 ± 4.9 0.58 ± 0.12 385.4 ± 42.5 5.7 ± 1.5
− 27.0 ± 7.6 13.0 ± 2.4 − 4.0 ± 0.6 − 2.2 ± 0.1 0.08 ± 0.0 − 201.1 ± 24.5 − 6.5 ± 1.6
31.0 ± 9.5 79.6 ± 9.8 49.6 ± 6.2 37.5 ± 5.0 0.50 ± 0.10 578.4 ± 67.0 12.24 ± 3.4
30.5 ± 8.9 81.5 ± 9.6 50.9 ± 7.2 38.5 ± 5.8 0.50 ± 0.09 560.0 ± 68.1 12.11 ± 3.6
− 0.05 ± 0.6 1.9 ± 0.2 − 1.3 ± 1.0 1.0 ± 0.8 0.0 ± 0.0 − 18.4 ± 3.6 − 0.13 ± 0.5
0.036 0.021 0.020 0.035 0.05 0.001 0.04
128.5 ± 11.5 83.5 ± 7.5
127.5 ± 11.0 81.0 ± 6.1
− 1.0 ± 0.5 − 2.5 ± 1.4
127.8 ± 12.0 82.9 ± 7.6
127.5 ± 11.6 82.3 ± 7.1
− 0.3 ± 0.4 − 0.6 ± 0.5
0.33 0.04
131.6 ± 12.5 85.5 ± 7.7 38.3 ± 4.0
128.5 ± 11.9 80.4 ± 7.0 34.2 ± 3.8
− 3.1 ± 0.6 − 5.1 ± 0.7 − 4.1 ± 0.2
130.9 ± 12.6 84.8 ± 7.8 38.5 ± 4.1
130.6 ± 12.4 84.2 ± 7.6 37.8 ± 4.0
− 0.3 ± 0.2 − 0.6 ± 0.2 − 0.7 ± 0.1
0.01 0.002 0.020
Values are represented as x ± SD. AHI, apnea–hypopnea index; hsCRP, high-sensitive C-reactive protein; LVEDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESd, left ventricular end-systolic diameter; ProBNP, prohormone of brain natriuretic peptide; SaO2, oxygen saturation. P-value refers to the comparison between the change in the treatment group and the change in the control group.
Comparison of secondary endpoints after 3 months between the treatment group and the control group
Table 3
Treatment group (n = 40) Cardiac death Nonfatal MI Hospitalization Composite endpoint
1 0 2 3
(2.5) (0) (5) (7.5)
Control group (n = 40) 1 1 7 9
(2.5) (2.5) (17.5) (22.5)
P-value 0.99 0.80 0.04 0.002
Values are represented as n (%). MI, myocardial infarction.
sympathetic nervous system activity [7], inflammatory response [8], and increased cardiac preload and afterload. When sleep apnea occurs, the sympathetic nervous system is activated, the catecholamine concentration increases, and the renin–angiotensin–aldosterone system is activated, which leads to increases in blood pressure and heart rate and increased cardiac work. In addition, intermittent hypoxia and repeated reoxygenation caused by OSAHS creates free oxygen radicals and results in inflammation with increased inflammatory mediators such as interleukin-6, tumor necrosis factor, and C-reactive protein, which may cause endothelial dysfunction in the blood vessels and worsening of myocardial ischemia. Hypoxia caused by the apnea can also lead to pulmonary artery vasoconstriction, pulmonary artery hypertension, and increased right ventricular afterload, thereby leading to right heart failure. Furthermore, OSAHS patients have greater upper airway resistance while sleeping and laborious breathing decreases the intrathoracic pressure, which in turn increases venous reflux and increases cardiac preload in the right heart chamber. An increase in right ventricular end-diastolic volume causes the septum to move to the left, which reduces left ventricular filling volume and compliance, leading to a reduction in stroke volume; furthermore, OSAHS patients often have high blood pressure, which increases left ventricular afterload.
In this study, patients with coronary heart disease combined with OSAHS were administered a noninvasive positive pressure ventilation therapy, and the resulting changes in blood pressure showed that the nocturnal blood pressures were markedly reduced compared with daytime pressures. The nocturnal systolic and diastolic blood pressures, however, decreased most significantly, decreasing 3.1 and 5.1 mmHg, respectively, in the treatment group, which was relatively high compared with a recent meta-analysis [9]. This indicates that noninvasive positive pressure ventilation therapy for coronary heart disease combined with OSAHS had a significant effect in lowering nocturnal blood pressures while having no significant effect on daytime blood pressure in patients without daytime sleepiness, which is in agreement with a previous report on CPAP treatments for solely OSAHS patients [10]. A study by Metoki et al. [11] showed that each additional 5% decrease in nocturnal blood pressure accounted for an ∼20% reduction in cardiovascular mortality. Data from observational studies and randomized trials have shown that if diastolic blood pressure decreased 2 mmHg in a population, the prevalence of hypertension would decrease by 17%, the risk of coronary heart disease would decrease by 6%, and the risk of stroke and transient ischemic attack would decrease by 15% [12]. The lower blood pressure significantly reduced cardiac afterload, reduced the workload of the heart, and improved the heart function. In addition, serum hsCRP concentration decreased significantly, suggesting that when the coronary heart disease/OSAHS patients were treated with noninvasive positive pressure ventilation therapy, less inflammatory mediators were released, thereby reducing blood vessel endothelial dysfunction and ameliorating the myocardial ischemia. In addition, the serum NT-ProBNP levels were significantly reduced and LVEDd as well as LVESd improved significantly in addition to significantly enhanced LVEF and reduced left atrial diameter (Table 2). Nishihata et al. [13] recently
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520 Coronary Artery Disease 2014, Vol 25 No 6
reported that CPAP therapy can improve the outcome of cardiovascular events in elderly patients with heart disease and OSAHS; the authors conducted a survey of the survival and hospitalization rates in 130 patients and found that CPAP therapy improved cardiovascular disease events, a result that is highly consistent with our study. However, Sun et al. [14] analyzed the results of 10 clinical trials before 2012 in which 259 patients were enrolled and found that although CPAP could significantly improve LVEF, especially for patients with both OSAHS and heart failure, its effect on patients with only OSAHS was relatively small and not statistically significant. Thus, the effectiveness of CPAP for lowering blood pressures can vary. This variation may be related to the CPAP treatment time. In this study, we treated patients for 3 h or more, but treatment throughout the night may lead to better effects in lowering blood pressures. The duration of our study was 3 months, which is similar to that of other published clinical trials. If OSA had been present long before it was diagnosed, the OSAinduced hypertension may not be reversible in such a short period of time, which may be another reason why our results differ from those of other studies. The secondary endpoint data presented in this study show that the cardiac death, nonfatal myocardial infarction, and hospitalization as a composite endpoint was clearly lower in the treatment group than in the control group. In particular, hospitalizations were fewer in the treatment group, which suggests that the quality of life improved significantly.
The authors thank all patients, their families, and physicians for their generous assistance. They also greatly appreciate the contributions from Dr Minpeng Wang.
Conclusion
10
Use of noninvasive mechanical ventilation therapy to treat patients with coronary heart disease combined with OSAHS could significantly reduce serum NT-ProBNP as well as hsCRP serum levels, reduce in particular nocturnal diastolic blood pressure, and improve cardiac structure and function, while reducing complications. Therefore, for patients with coronary heart disease combined with OSAHS, the medication treatment can be improved by long-term noninvasive mechanical ventilation.
Acknowledgements This work was supported by a grant from the Project of Shanghai Municipal Health Bureau (20114328).
Conflicts of interest
There are no conflicts of interest.
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Cardiac structure and function improvements in coronary artery disease combined with severe obstructive sleep apnea/hypopnea syndrome patients via noninvasive positive pressure ventilation therapy Xinbing Liua, Liuliu Fenga, Guoliang Caob, Hongman Huanga, Qitan Xua, Jianhua Yua, Shufu Zhanga and Mingcheng Zhouc Objective The aim of this study was to investigate the effects of a noninvasive positive pressure ventilation therapy on cardiac structure and function in patients with coronary heart disease combined with obstructive sleep apnea/hypopnea syndrome (OSAHS). Patients and methods Eighty patients with coronary heart disease OSAHS were divided randomly into treatment (n = 40) and control (n = 40) groups. Both groups received standard medications. The treatment group received additional noninvasive mechanical ventilation support for at least 3 h (3–6 h) every night. On the first day after selection and 3 months afterwards, participants were examined with echocardiograms, 24-h ambulatory blood pressure monitoring, and blood analyses. Primary endpoints were left ventricular end-diastolic diameter, left ventricular endsystolic diameter, left ventricular ejection fraction, left atrial diameter as well as serum concentrations of N-terminal prohormone of brain natriuretic peptide, and high-sensitive C-reactive protein. Secondary endpoints included cardiac death, nonfatal myocardial infarction, and hospitalization. Results After the 3-month study period, patients in the treatment group showed significantly improved left ventricular end-diastolic diameter (P = 0.02), left ventricular end-systolic diameter (P = 0.035), left ventricular ejection
Introduction Obstructive sleep apnea/hypopnea syndrome (OSAHS) is a condition characterized by recurrent sleep apnea and hypopnea, and is categorized as a sleep disorder. OSAHS can cause damage to multiple organs, especially the cardiovascular system, leading to deterioration in cardiac structures and function [1,2], and 56% of OSAHS patients show abnormal left ventricular filling patterns often accompanied by higher left ventricular volume and a thickening of the septum and the left ventricular posterior wall. The incidence of heart failure is 2.38 times greater in OSAHS patients than in the nonaffected population, markedly impacting the life expectancy and quality of life of these patients [3,4]. Noninvasive mechanical ventilation is mainly used in patients with chronic obstructive pulmonary disease, neuromuscular disorders, and obstructive sleep apnea (OSA) [5]. During this procedure, the ventilator provides synchronized 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
fraction (P = 0.05), and left atrial diameter (P = 0.02) values, and their serum N-terminal prohormone of brain natriuretic peptide (P = 0.01) and high-sensitive C-reactive protein (P = 0.04) concentrations were significantly improved compared with the control group. During the 3 months, three cardiovascular complications occurred in the treatment group versus nine in the control group (P < 0.05). Conclusion For patients with coronary heart disease combined with OSAHS, noninvasive mechanical ventilation therapy can significantly improve heart functions and reduce the occurrence of cardiovascular complications. Coron Artery Dis 25:516–520 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2014, 25:516–520 Keywords: cardiac structure and function, continuous positive pressure noninvasive mechanical ventilation, obstructive sleep apnea/hypopnea syndrome, stable coronary artery disease a
Department of Cardiology, Shanghai Shi Dong Hospital, bDepartment of Geriatrics, Shanghai No. 3 People’s Hospital and cDepartment of Cardiology, An Tu Hospital, Shanghai, China Correspondence to Mingcheng Zhou, MD, Department of Cardiology, An Tu Hospital, No. 200 Yanji East Road, Shanghai 200093, China Tel/fax: + 86 21 65489845; e-mail: [email protected] Received 17 February 2014 Revised 18 April 2014 Accepted 29 April 2014
positive airway pressure when patients inhale, which can effectively help overcome airway resistance and reduce the amount of work done by the patient for breathing, thereby effectively improving their respiratory function. When patients exhale, the ventilator can provide a lower positive pressure, reducing or offsetting the patient’s workload, which can effectively reduce fatigue. The current clinical practice in China for the treatment of OSAHS patients with coronary heart disease is still only medication. We hypothesized that for patients with coronary heart disease combined with OSAHS, a noninvasive mechanical ventilation therapy, otherwise used in China only for chronic obstructive pulmonary disease treatment, may have a beneficial impact on cardiac structure and function as an added measure combined with common medications. In this prospective study, we investigated whether or not adding a noninvasive mechanical ventilation therapy to the standard drug DOI: 10.1097/MCA.0000000000000129
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Noninvasive pressure ventilation for OSAHS Liu et al. 517
treatment for stable coronary artery disease combined with OSAHS patients could improve their outcome.
Patients and methods Definition of apnea
Apnea is defined as an interruption to normal airflow of at least 10 s. Hypopnea is diagnosed when one or both of the following conditions are fulfilled: (a) decreased airflow of at least 30% and decreased oxygen saturation of at least 4% compared with baseline levels for at least 10 s; (b) decreased airflow of at least 50% and decreased oxygen saturation of at least 3% compared with the baseline for at least 10 s, or sudden awakening. The severity of sleep apnea is usually determined by the apnea–hypopnea index (AHI), which is the sum of the average number of episodes of apnea and hypopnea per hour of recorded sleep. Mild sleep apnea refers to patients with an AHI of 5–15 times/h of sleep, moderate sleep apnea refers to patients with an AHI of 15–30 times/h of sleep, and severe sleep apnea refers to patients with an AHI greater than 30 times/h of sleep [6]. Patients
All patients in this study, including inpatients and outpatients, were hospitalized in one of three Shanghai hospitals between March 2010 and March 2013 (Shanghai East Hospital, Shanghai An Tu Hospital’s Department of Cardiology, and Shanghai No. 3 People’s Hospital’s geriatric clinics). Inclusion criteria were as follows: (a) male and female patients of any ethnicity between the age of 40 and 75 years; (b) confirmed coronary artery disease including at least one of the following criteria: myocardial infarction in the past (≥90 days before signing the informed consent), coronary angiography showing a 50% or more stenosis in at least one major coronary artery, 64-slice or more spiral computed tomography (Light Speed VCT, Forchheim, Germany) showing 50% or more stenosis in at least one major coronary artery, at least one blood vessel received by percutaneous transluminal coronary angioplasty and/or a percutaneous coronary intervention (≥90 days before signing of informed consent) as well as multiple blood vessels received by coronary artery bypass graft therapy (≥1 year before signing of informed consent); and (c) patients had moderate to severe OSA with an AHI of greater than 15 times/h of sleep, with overnight monitoring showing that oxygen saturation decreased by at least 4% of at least 12 times/h and measured resting awake oxygen saturation of at least 90%. Patients were excluded if they fulfilled any of the following criteria: (a) the doctor or researcher responsible believed that the patient should not participate in the study for any reason, such as severe disability, death likely within the next 2 years, significant memory, perceptual, or behavioral disorders, neurological defects (such as limb paralysis) impeding independent use of the continuous positive airway pressure (CPAP) mask, any planned coronary or peripheral revascularization within
the next 3 months, New York Heart Association heart failure classification class IV, stroke caused by subarachnoid hemorrhage, or previous use of CPAP to treat OSA. Of 110 patients who were screened, 91 patients fulfilled the inclusion criteria; however, six patients declined to sign an informed consent form and were therefore excluded. The remaining 85 patients were divided randomly into either the treatment or the control group. During the course, however, two patients in the treatment group could not tolerate the ventilator therapy plus one patient could not adhere to the required 3 h of use per night. In the control group, one patient purchased a ventilator and used it privately and one patient was lost because of moving. Thus, for the statistical analyses, the treatment group (n = 40) and a control group (n = 40) were included. This study was approved by the Shanghai East Hospital Ethics Committee and each participant signed informed consent. Treatments
The medications for all patients are listed in Table 1. Use of ventilator: all treatment group patients were provided noninvasive ventilator support (S9 Autoset; ResMed, Sydney, New South Wales, Australia) with appropriate masks (Full Face Mirage Quattro masks; ResMed) using the CPAP method, with a respiratory frequency of Comparison of basic data between the treatment group and the control group
Table 1
Items
Treatment group (n = 40)
Age (years) 62.86 ± 9.0 Males 30 (75.0) Hypertension 35 (87.5) Type 2 diabetes 10 (25) 2 BMI (kg/m ) 25.0 ± 4.5 NYHA heart function classification Class I 15 (37.5) Class II 18 (45.0) Class III 7 (17.5) Daytime mean blood pressure (mmHg) Systolic pressure 128.5 ± 11.5 Diastolic pressure 83.5 ± 7.5 Nocturnal mean blood pressure (mmHg) Systolic pressure 131.5 ± 12.5 Diastolic pressure 85.5 ± 7.7 hsCRP (mg/l) 12.20 ± 3.5 Prior medical history Smoking 12 (30.0) Myocardial 5 (12.5) infarction PCI 10 (25.0) CABG 0 (0) Stroke 3 (7.5) Drug treatment ACEI or ARB 30 (75.0) Statins 34 (85.0) Aspirin 38 (95.0) β-Blockers 31 (77.5)
Control group (n = 40)
P-value
63.14 ± 9.1 28 (70.0) 36 (90.0) 12 (30.0) 25.5 ± 4.0
0.476 0.198 0.860 0.428 0.745
13 (32.5) 19 (47.5) 8 (20.0)
0.350 0.618 0.339
127.8 ± 12.0 82.9 ± 7.6
0.830 0.745
130.9 ± 12.6 84.8 ± 7.8 12.04 ± 3.4
0.910 0.890 0.856
10 (25.0) 4 (10.0)
0.096 0.780
8 (20.0) 0 (0) 2 (5.0)
0.180 1 0.890
28 36 36 33
(70.0) (90.0) (90.0) (82.5)
0.578 0.610 0.650 0.680
Values are represented as x ± SD or n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft; hsCRP, high-sensitive C-reactive protein; NYHA, New York Heart Association; PCI, percutaneous coronary intervention.
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518 Coronary Artery Disease 2014, Vol 25 No 6
12–16 breaths/min and a pressure of 6–12 cmH2O. The instrument setting was adjusted to achieve sleep time snoring and airflow reduction of 95% and AHI of less than 5 times/h of sleep by ventilation monitoring. Outcome measurements
Primary endpoints were left ventricular end-diastolic diameter (LVEDd), left ventricular end-systolic diameter (LVESd), left ventricular ejection fraction (LVEF), left atrial diameter and serum concentrations of N-terminal prohormone of brain natriuretic peptide (NTProBNP), a biomarker for congestive heart failure, as well as high sensitive C-reactive protein (hsCRP) as an indicator for cardiovascular disease progression. A SONOS 7500 cardiac ultrasound machine (Philips, Washington, USA) was used for cardiac structure examination. Peripheral blood (3 ml) was collected from the patients’ median cubital vein, mixed with a disodium edetate (EDTA) solution containing aprotinin in an anticoagulant tube, and centrifuged at 3000 rpm for 15 min within 12 h of collection. The serum was separated and stored at − 70°C until use to avoid repeated freeze–thaw cycles. Serum NT-ProBNP levels were detected using an enzyme-linked immunosorbent assay kit (Roche, Shanghai, China) and hsCRP was determined using a latex-enhanced nephelometry kit (Siemens Ltd). In addition, 24-h ambulatory blood pressure monitoring was performed using an ambulatory blood pressure monitoring instrument and an APN portable sleep monitoring device (ResMed) was used for sleep monitoring. The ventilators used were ResMed Autoset-T automatic pressure-regulating ventilators (ResMed). All patients were monitored on day 1 and after 3 months of noninvasive mechanical ventilation. Secondary endpoints were cardiac death, nonfatal myocardial infarction, and hospitalization. Statistical analyses
SPSS 16.0 statistical analysis software (SPSS Inc., Chicago, Illinois, USA) was used for all analyses. Quantitative data are shown as mean ± SD (x ± SD). Group t-tests were used for baseline comparisons between treatment and control groups and normally distributed data. Two-sample rank tests and Mann–Whitney U-tests were used for non-normally distributed data. Percentages between the two groups were compared using χ2-test or precise probability test. Pretherapy and follow-up data between groups were compared using analysis of variance. A P-value of less than 0.05 was considered statistically significant.
Results Changes in cardiac structure and function during treatment
Forty patients from the treatment group were included in the analysis, 30 men and 10 women, mean age of 62.86 ± 9.0 years; the 40 patients in the control group
included 28 men and 12 women, mean age of 63.14 ± 9.1 years. Comparison of the basic characteristics between the treatment group and the control group showed no statistically significant differences (Table 1). Comparisons between patients in the treatment group and patients in the control group showed that LVEDd (P = 0.02) and LVESd (P = 0.035) were significantly better in the treatment group, indicating a beneficial change of the cardiac structure. In addition, patients in the treatment group receiving noninvasive mechanical ventilation showed a statistically significant improvement in LVEF (P = 0.05), indicating that they achieved superior heart function improvement. The left atrial diameter was also significantly reduced in the treatment group compared with the control group (P = 0.02; Table 2). Biomarker changes during treatment
Serum NT-ProBNP concentrations in the treatment group were 586.5 ± 67.8 pg/ml at day 1 and 385.4 ± 42.5 pg/ml after 3 months and in the control group they were 578.4 ± 67.0 pg/ml at day 1 and 560.0 ± 68.1 pg/ml after 3 months. The treatment group experienced a greater reduction and the difference compared with the change in the control group was statistically significant (P = 0.001). The hsCRP serum concentrations in the treatment group were 12.20 ± 3.5 mg/l at day 1 and 5.7 ± 1.5 mg/l after 3 months and those in the control group were 12.24 ± 3.4 mg/l at day 1 and 12.11 ± 3.6 mg/l after 3 months. The reduction in the treatment group was significantly better than that in the control patients (P = 0.04; Table 2). Changes in ambulatory blood pressure before and after treatment
On comparing the daytime mean blood pressures between the two groups, only the diastolic pressure decreased significantly more in the treatment group compared with the control group (P = 0.04). Both the nocturnal mean diastolic (P = 0.01) and the systolic (P = 0.002) pressures, however, were reduced in the treatment group to a significantly higher extent compared with the control patients. Secondary endpoint events
During the 3 months of the study, there were a total of 12 complications in the two groups; three occurred in the treatment group (3/43) and nine in the control group (9/42), and the difference was statistically significant (Table 3). The reasons for hospitalization were cardiac events including acute coronary syndrome, heart failure, and cardiac embolism, accompanied by severe arrhythmia symptoms.
Discussion OSAHS can induce changes in cardiac structure and function through a variety of factors: enhanced
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Noninvasive pressure ventilation for OSAHS Liu et al. 519
Table 2
Comparison of the treatment group and the control group data at day 1 and after 3 months Treatment group (n = 40)
AHI mSaO2 LVEDd (mm) LVESd (mm) LVEF ProBNP (pg/ml) hsCRP (mg/l) Daytime mean blood pressure Systolic Diastolic Nocturnal mean blood pressure Systolic Diastolic Left atrial diameter (mm)
Control group (n = 40)
Day 1
3 months
Change
Day 1
3 months
Change
P-value
30.2 ± 10.2 79.2 ± 9.6 49.6 ± 6.7 37.6 ± 5.0 0.50 ± 0.11 586.5 ± 67.8 12.20 ± 3.5
3.2 ± 2.6 92.2 ± 7.2 45.6 ± 5.9 35.4 ± 4.9 0.58 ± 0.12 385.4 ± 42.5 5.7 ± 1.5
− 27.0 ± 7.6 13.0 ± 2.4 − 4.0 ± 0.6 − 2.2 ± 0.1 0.08 ± 0.0 − 201.1 ± 24.5 − 6.5 ± 1.6
31.0 ± 9.5 79.6 ± 9.8 49.6 ± 6.2 37.5 ± 5.0 0.50 ± 0.10 578.4 ± 67.0 12.24 ± 3.4
30.5 ± 8.9 81.5 ± 9.6 50.9 ± 7.2 38.5 ± 5.8 0.50 ± 0.09 560.0 ± 68.1 12.11 ± 3.6
− 0.05 ± 0.6 1.9 ± 0.2 − 1.3 ± 1.0 1.0 ± 0.8 0.0 ± 0.0 − 18.4 ± 3.6 − 0.13 ± 0.5
0.036 0.021 0.020 0.035 0.05 0.001 0.04
128.5 ± 11.5 83.5 ± 7.5
127.5 ± 11.0 81.0 ± 6.1
− 1.0 ± 0.5 − 2.5 ± 1.4
127.8 ± 12.0 82.9 ± 7.6
127.5 ± 11.6 82.3 ± 7.1
− 0.3 ± 0.4 − 0.6 ± 0.5
0.33 0.04
131.6 ± 12.5 85.5 ± 7.7 38.3 ± 4.0
128.5 ± 11.9 80.4 ± 7.0 34.2 ± 3.8
− 3.1 ± 0.6 − 5.1 ± 0.7 − 4.1 ± 0.2
130.9 ± 12.6 84.8 ± 7.8 38.5 ± 4.1
130.6 ± 12.4 84.2 ± 7.6 37.8 ± 4.0
− 0.3 ± 0.2 − 0.6 ± 0.2 − 0.7 ± 0.1
0.01 0.002 0.020
Values are represented as x ± SD. AHI, apnea–hypopnea index; hsCRP, high-sensitive C-reactive protein; LVEDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESd, left ventricular end-systolic diameter; ProBNP, prohormone of brain natriuretic peptide; SaO2, oxygen saturation. P-value refers to the comparison between the change in the treatment group and the change in the control group.
Comparison of secondary endpoints after 3 months between the treatment group and the control group
Table 3
Treatment group (n = 40) Cardiac death Nonfatal MI Hospitalization Composite endpoint
1 0 2 3
(2.5) (0) (5) (7.5)
Control group (n = 40) 1 1 7 9
(2.5) (2.5) (17.5) (22.5)
P-value 0.99 0.80 0.04 0.002
Values are represented as n (%). MI, myocardial infarction.
sympathetic nervous system activity [7], inflammatory response [8], and increased cardiac preload and afterload. When sleep apnea occurs, the sympathetic nervous system is activated, the catecholamine concentration increases, and the renin–angiotensin–aldosterone system is activated, which leads to increases in blood pressure and heart rate and increased cardiac work. In addition, intermittent hypoxia and repeated reoxygenation caused by OSAHS creates free oxygen radicals and results in inflammation with increased inflammatory mediators such as interleukin-6, tumor necrosis factor, and C-reactive protein, which may cause endothelial dysfunction in the blood vessels and worsening of myocardial ischemia. Hypoxia caused by the apnea can also lead to pulmonary artery vasoconstriction, pulmonary artery hypertension, and increased right ventricular afterload, thereby leading to right heart failure. Furthermore, OSAHS patients have greater upper airway resistance while sleeping and laborious breathing decreases the intrathoracic pressure, which in turn increases venous reflux and increases cardiac preload in the right heart chamber. An increase in right ventricular end-diastolic volume causes the septum to move to the left, which reduces left ventricular filling volume and compliance, leading to a reduction in stroke volume; furthermore, OSAHS patients often have high blood pressure, which increases left ventricular afterload.
In this study, patients with coronary heart disease combined with OSAHS were administered a noninvasive positive pressure ventilation therapy, and the resulting changes in blood pressure showed that the nocturnal blood pressures were markedly reduced compared with daytime pressures. The nocturnal systolic and diastolic blood pressures, however, decreased most significantly, decreasing 3.1 and 5.1 mmHg, respectively, in the treatment group, which was relatively high compared with a recent meta-analysis [9]. This indicates that noninvasive positive pressure ventilation therapy for coronary heart disease combined with OSAHS had a significant effect in lowering nocturnal blood pressures while having no significant effect on daytime blood pressure in patients without daytime sleepiness, which is in agreement with a previous report on CPAP treatments for solely OSAHS patients [10]. A study by Metoki et al. [11] showed that each additional 5% decrease in nocturnal blood pressure accounted for an ∼20% reduction in cardiovascular mortality. Data from observational studies and randomized trials have shown that if diastolic blood pressure decreased 2 mmHg in a population, the prevalence of hypertension would decrease by 17%, the risk of coronary heart disease would decrease by 6%, and the risk of stroke and transient ischemic attack would decrease by 15% [12]. The lower blood pressure significantly reduced cardiac afterload, reduced the workload of the heart, and improved the heart function. In addition, serum hsCRP concentration decreased significantly, suggesting that when the coronary heart disease/OSAHS patients were treated with noninvasive positive pressure ventilation therapy, less inflammatory mediators were released, thereby reducing blood vessel endothelial dysfunction and ameliorating the myocardial ischemia. In addition, the serum NT-ProBNP levels were significantly reduced and LVEDd as well as LVESd improved significantly in addition to significantly enhanced LVEF and reduced left atrial diameter (Table 2). Nishihata et al. [13] recently
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520 Coronary Artery Disease 2014, Vol 25 No 6
reported that CPAP therapy can improve the outcome of cardiovascular events in elderly patients with heart disease and OSAHS; the authors conducted a survey of the survival and hospitalization rates in 130 patients and found that CPAP therapy improved cardiovascular disease events, a result that is highly consistent with our study. However, Sun et al. [14] analyzed the results of 10 clinical trials before 2012 in which 259 patients were enrolled and found that although CPAP could significantly improve LVEF, especially for patients with both OSAHS and heart failure, its effect on patients with only OSAHS was relatively small and not statistically significant. Thus, the effectiveness of CPAP for lowering blood pressures can vary. This variation may be related to the CPAP treatment time. In this study, we treated patients for 3 h or more, but treatment throughout the night may lead to better effects in lowering blood pressures. The duration of our study was 3 months, which is similar to that of other published clinical trials. If OSA had been present long before it was diagnosed, the OSAinduced hypertension may not be reversible in such a short period of time, which may be another reason why our results differ from those of other studies. The secondary endpoint data presented in this study show that the cardiac death, nonfatal myocardial infarction, and hospitalization as a composite endpoint was clearly lower in the treatment group than in the control group. In particular, hospitalizations were fewer in the treatment group, which suggests that the quality of life improved significantly.
The authors thank all patients, their families, and physicians for their generous assistance. They also greatly appreciate the contributions from Dr Minpeng Wang.
Conclusion
10
Use of noninvasive mechanical ventilation therapy to treat patients with coronary heart disease combined with OSAHS could significantly reduce serum NT-ProBNP as well as hsCRP serum levels, reduce in particular nocturnal diastolic blood pressure, and improve cardiac structure and function, while reducing complications. Therefore, for patients with coronary heart disease combined with OSAHS, the medication treatment can be improved by long-term noninvasive mechanical ventilation.
Acknowledgements This work was supported by a grant from the Project of Shanghai Municipal Health Bureau (20114328).
Conflicts of interest
There are no conflicts of interest.
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