- Email: [email protected]
Lipoprotein-associated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome
Journal Pre-proof Lipoprotein-associated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome Chenyu Xu, Fenfang Yu, Shan Mao, Ying Shi, Qian Li, Surong Fang, Yan Tan, Wei Gu, Liang Ye PII:
S0954-6111(20)30021-4
DOI:
https://doi.org/10.1016/j.rmed.2020.105881
Reference:
YRMED 105881
To appear in:
Respiratory Medicine
Received Date: 6 December 2019 Revised Date:
20 January 2020
Accepted Date: 26 January 2020
Please cite this article as: Xu C, Yu F, Mao S, Shi Y, Li Q, Fang S, Tan Y, Gu W, Ye L, Lipoproteinassociated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2020.105881. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
XCY drafted the article or revised it critically for important intellectual content; YFF, MS, SY, LQ, FSR, TY made contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data; GW, YL finally approved the version to be submitted.
Lipoprotein-associated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome Chenyu Xu#, Fenfang Yu#, Shan Mao, Ying Shi, Qian Li, Surong Fang, Yan Tan, Wei Gu*, Liang Ye* Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China #
These authors contributed equally to this work.
Correspondence to: Liang Ye, Department of Respiration, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Qinhuai District, Nanjing 210006, China. Tel.: +86-25-87726230; Email: [email protected] Wei Gu, Department of Respiration, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Qinhuai District, Nanjing 210006, China. Tel.: +86-25-87726231; Email: [email protected]
1
Abstract Background: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease (CVD). As a new inflammatory biomarker of CVD, rare attention has been paid to the roles of lipoprotein-associated phospholipase (Lp-PLA2) in OSAS studies. In this study, we aimed to investigate the correlation between Lp-PLA2 and concomitant CVD in OSAS patients. Methods: In this prospective study, 152 OSAS patients were further divided into mild, moderate, and severe OSAS subgroups. They presented heart failure, coronary artery disease, or arrhythmia were confirmed with CVD. Thirty-one subjects without OSAS were recruited for the control group. The relationship between Lp-PLA2 and concomitant CVD in OSAS patients was analyzed. Results: Serum Lp-PLA2 values were significantly higher in the severe and moderate OSAS group compared with mild OSAS and OSAS negative groups (P=0.025). Significant increase was noticed in serum Lp-PLA2 levels in CVD patients compared with those without in severe-moderate-mild OSAS (P<0.05). In logistic regression analysis, the level of Lp-PLA2 was proved as a significant independent predictor for CVD (OR =1.117, P=0.008). The ROC analysis indicated that the best cut-off value of Lp-PLA2 for predicting CVD in OSAS patients was 238.09 ng/ml. The positive and negative predictive values were 72.5% and 70.5%, respectively. The sensitivity was 46.8% and the specificity was 87.8%. Conclusions: Lp-PLA2 might be associated with the severity of OSAS and the occurrence of CVD in OSAS patients. Lp-PLA2 is expected to be a promising biomarker candidate in predicting CVD in patients with OSAS due to test convenience. Keywords:
Obstructive
sleep
apnea
syndrome
(OSAS);
lipoprotein-associated phospholipase (Lp-PLA2); biomarker
2
cardiovascular
disease
(CVD);
Introduction Obstructive sleep apnea syndrome (OSAS), a common disorder featured by repetitive episodes of nocturnal breathing cessation, is reported to significantly increase the risk of cardiovascular diseases (CVD) including hypertension[1, 2], heart failure[3, 4], arrhythmia, coronary artery disease (CAD)[5, 6]. OSAS patients usually present chronic intermittent hypoxemia and sleep fragmentation, which may trigger diverse syndromes by modulating various signaling pathways[7]. To our best knowledge, patients with sleep apnea frequently show sympathetic activation, oxidative stress, and metabolic dysregulation, suggesting a possible link between OSAS and CVD [8]. Recently, much attention has been paid to lipoprotein-associated phospholipase A2 (Lp-PLA2) serving as an independent risk factor for CVD [9, 10]. Lp-PLA2 is an inflammatory enzyme produced by monocytes, macrophages and T lymphocytes, which is up-regulated in atherosclerotic plaques[11]. It has been proved to show high specificity for vascular inflammation unlike the other systemic inflammation. Lp-PLA2 elevation or activation could predict both primary and recurrent coronary or cardiovascular events in the general population[12, 13]. To date, a few studies have investigated the roles of Lp-PLA2 in OSAS patients[14-16]. However, little is known about the association between Lp-PLA2 and CVD occurrence in OSAS patients. This study was designed to evaluate the correlation between serum Lp-PLA2 levels and cardiovascular events in OSAS patients. In addition, we investigated the efficiency of Lp-PLA2 as a marker for predicting CVD in OSAS patients. Material and methods Patients In this study, we included patients presented to the Sleep Disorders Center at Nanjing First Hospital due to sleep-disordered breathing problems from September 2014 to January 2019. All subjects underwent overnight polysomnography (PSG) and were recruited after signing an institutional ethics committee-approved consent form. The average apneas and hypopneas per hour of sleep was defined as the apnea-hypopnea index (AHI). The diagnosis and severity of OSAS was based on the following criteria recommended by the American Academy of Sleep Medicine: OSAS negative group (AHI < 5), mild OSAS group (5 ≤ AHI < 15), moderate OSAS group (15 ≥ AHI < 30) and severe OSAS group (AHI ≥ 30). The exclusion criteria were as follows: those with central sleep apnea syndrome, upper airway resistant syndrome, and narcolepsy or movement disorder; those received 3
treatment for OSAS, CVD, hypoxemic lung disease, hematologic disease, liver or kidney disease, chronic alcoholism, malignancy, pregnancy, acute and/or chronic infection, or autoimmune disease previously. Demographic characteristics, sleep, and medical history, including cardiovascular and metabolic diseases, medication, and habits were obtained based on a standardized questionnaire. CVD was defined according to the presence of heart failure, coronary artery disease or arrhythmia. The demographic characteristics [e.g. (body mass index)] and laboratory evaluation were performed including routine blood tests (e.g. fasting glucose, liver enzymes, lipid profile), respiratory function tests, and electrocardiogram. Each patient signed the informed consent. The study protocols were approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University. A BMI of >30 kg/m2 was defined as obese. Hyperlipidemia was defined as follows: serum low-density lipoprotein cholesterol (HDL-c) of ≥4.1 mmol/L; or total cholesterol (TC) of >6.2mmol/L; or triglyceride (TG) of ≥2.3 mmol/L; or high-density lipoprotein cholesterol (HDL-c) of <1.0 mmol/L[17]. Blood pressure was measured at the non-dominant arm in the morning of the procedure after a 5 min interval. Hypertension was defined based on the standards proposed by 2007 European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) task force for the management of arterial hypertension guidelines[18]. PSG evaluation The presence or absence of OSAS was based on the standard polysomnography System (Philips Respironics, Murrayvile, PA) with Alice Sleepware Software. PSG data were analyzed manually by a respiratory physiologist using the Irish Sleep Society/AASM guidelines. Obstructive apnea was defined as a drop in airflow to ≤ 90% of baseline for ≥ 10s as recorded with the oronasal sensor. Hypopnea was defined as a drop in airflow ≥ 30% from baseline as recorded with the nasal cannula for ≥ 10s accompanied by ≥ 3% oxygen desaturation or an arousal. PSG parameters including the oxygen desaturation index (ODI), minimal arterial oxygen saturation (MiniSaO2), mean O2 saturation (SaO2), time spent below 90% oxygen saturation (TS90%) and arousal index were also recorded using standard PSG System (Philips Respironics, Murrayvile, PA). Laboratory analysis Fasting blood samples were collected in the morning after PSG monitoring. Serum samples were obtained from patients using a serum separator tube and allowed to clot for two hours at room temperature before centrifugation for 20 min at 1000 g. Then the samples were frozen and stored at 4
-80°C until analysis. Serum Lp-PLA2 levels were measured using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction (Kangerke Biotech, Tianjin, China). Levels of lipids including TC, HDL-c, calculated LDL-c, and TG were assessed with a Flex reagent cartridge (Date Behring, Newark, DE). Statistical analysis The
distribution
of
continuous
variables
for
normality
was
tested
with
One-Sample
Kolmogorov-Smirnov test. The data were presented as mean ± standard deviation (SD), or median and interquartile ranges. Categorical variables were presented as frequencies and percentages. The normal distribution of continuous variables was evaluated using the Shapiro-Wilks test. According to continuous variables with normal distribution or not, the continuous variables among the groups were compared using one-way analysis of variance (ANOVA) or Kruskal-Wallis test. In one-way ANOVA for post hoc multiple comparison, Student-Newman-Keuls (SNK) test was used. Nemenyi test was performed for the multiple comparisons in Kruskal-Wallis test. Based on continuous variables with normal distribution or not, continuous variables between OSAS without CVD and OSAS with CVD groups were compared using two independent sample t tests or Mann-Whitney U tests. Continuous variables were expressed as mean (standard deviation) for the one-way ANOVA or two independent sample t-tests. For the Kruskal-Wallis test and Mann-Whitney U test, continuous variables were expressed as median (interquartile range). Chi square test was conducted for the analysis categorical variables. The independent predictors related to CVD in OSAS was determined using multiple logistic regression analysis. The predictive validity and optimal Lp-PLA2 cut-off value were estimated using the receiver-operating characteristic (ROC) curve. Data were analyzed using SPSS 18.0 software (IBM, Chicago, IL, USA). P value of <0.05 was considered statistically significant. Results A total of 183 patients met the selection criteria were included in the analysis. Demographic and biochemical data were presented in Table 1. Among these cases, 152 participants were diagnosed as OSAS, while 31 patients with an AHI of < 5 served as the OSAS negative group. As expected, there were statistical differences between the desaturation index, minimum oxygen saturation and mean oxygen saturation between these two groups (P<0.001, Table 1). The prevalence of CVD in the patients of severe OSAS group was significantly higher than that of the moderate and mild OSAS groups, as well as the OSAS negative group (P=0.039, Table 1). Serum 5
TG levels in severe OSAS group were significantly higher than the OSAS negative group, mild and moderate OSAS groups (P<0.001; Table 1). TC levels of OSAS patients were significantly higher than non-OSAS patients (P=0.001; Table 1). Meanwhile, Lp-PLA2 values were significantly higher in the severe and moderate OSAS group compared with mild OSAS and OSAS negative groups (P=0.025, Table 1). In Table 2, we further compared the differences of the clinical, laboratory and PSG data between OSAS patients with (n=62) and without CVD (n=90). OSAS patients with CVD showed higher AHI and ODI (P<0.05). Meanwhile, the Lp-PLA2 values of OSA patients with CVD were significantly higher than those without CVD (P=0.033, Table 2). Moreover, based on the grouping given by disease severity, our data showed that serum Lp-PLA2 levels were significantly higher in patients with CVD compared with those without in mild, moderate and severe OSAS groups (Fig. 1, P < 0.05). Finally, potential determinants for the CVD were investigated. In the logistic regression analysis for the risk factors of CVD among OSAS patients, Lp-PLA2 was determined as an independent predictor of CVD (OR =1.117, 95% CI: 1.002–1.252, P=0.008, Table 3). For the prediction of CVD in OSAS patients, the ROC curve analysis performed the cut-off value of Lp-PLA2 (>238.09) showed a sensitivity of 46.8% and a specificity of 87.8%. The positive predictive value and negative predictive value was 72.5% and 70.5%, respectively. The area under the curve value (AUC) was 0.716 (95% CI: 0.633–0.799, P<0.001; Figure 2). Discussion There were two novel findings in this study. First, serum Lp-PLA2 levels were significantly higher in a proportional manner with the deterioration of OSAS conditions. Second, Lp-PLA2 was proved as an independent predictor for OSAS cases with CVD. Cardiovascular complications, including hypertension, coronary artery disease, cardiac failure, cardiac arrhythmia, ventricular dysfunction, and pulmonary hypertension[19, 20], are the most serious complications of the patients with OSAS[21]. Nowadays, the mechanisms of impairment in myocardial contraction and relaxation among OSAS patients are still not well defined. Nevertheless, OSAS has been reported to be associated with the cardiac risks due to the derangement of the relation between myocardial oxygen demand and supply as a result of hypoxia, hypercapnia, increased sympathetic activation during apnea, and oxygen desaturation periods associated with apnea [22]. Intermittent episodes of hypoxia as a result of transient cessation of breathing during sleep were major physiologic 6
characteristics of OSAS and were resemble ischemia–reperfusion injury. Intermittent nocturnal hypoxemia induced the production of oxygen-free radicals, causing a state of low-grade circulation and local inflammation[23, 24]. These results demonstrated that inflammation and oxidative stress were important factors in the pathogenesis of cardiovascular complications in OSAS cases. Lp-PLA2 is a serine lipase mainly produced by activated monocytes and macrophages[25]. In the bloodstream, 1/3 of Lp-PLA2 circulates bound to HDLs and the other 2/3 to LDLs, with protein B100 serving as the mediator [26]. Lp-PLA2 entered the vessel wall and catalyzed the hydrolysis of the phospholipids
on
the
surface
of
the
LDLs,
which
then
resulted
in
the
release
of
lysophosphatidylcholine and oxidized fatty acids. These mediators triggered the inflammatory cascade, induced the chemotaxis of leucocytes into the sub-intimal space of the arterial wall and converted them into foam cells. As a consequence, Lp-PLA2 enhanced the growth and the instability of the lipid core of the atherosclerotic plaques, which consequently led to acute cardiovascular events [27-29]. Several studies have confirmed the roles of Lp-PLA2 as a predictor of CVD morbidity and mortality in apparently healthy populations, in diabetic and dysmetabolic patients and those with cardiac disease[30, 31]. Based on this evidence, the guidelines of three major heart international societies, the American College of Cardiology, the American Heart Association and the European Society of Cardiology, have included Lp-PLA2 activity measurement in the risk stratification of asymptomatic patients in order to optimize the lipid lowering therapy[32]. To date, few studies have investigated the roles of Lp-PLA2 in OSAS. In a previous study, Moise et al. found that serum Lp-PLA2 levels were higher in OSAS patients with metabolic syndrome than those without [16]. Besides, Barcelo et al evaluated the antioxidant capacity in male patients with OSAS, which demonstrated decrease of total antioxidant capacity and increase of Lp-PLA2 values among these patients [14]. This implicated oxidative stress as a contributing factor in the development of cardiac complications in cases with OSAS. In our study, the levels of Lp-PLA2 were higher in those with severe OSAS. This might explain the higher incidence of cardiovascular complications in cases with severe OSAS. In fact, the most important observation of the study was that we proved significantly higher levels of Lp-PLA2 in cases with CVD compared to those without. The Lp-PLA2 level was revealed to be an independent predictor for CVD in cases with OSAS. In addition, we herein found that Lp-PLA2 of 238.09 ng/ml could predict CVD occurrence in patients with OSAS, with the sensitivity of 46.8%, a specificity of 87.8%, and positive and negative predictive values of 72.5% and 7
70.5%, respectively. Our study yielded important outcomes in that it was conducted in a relatively larger patient population and emphasized the importance of Lp-PLA2 in the prediction of CVD in OSAS cases. However, there are some limitations of our study that we have to mention. First, this is a cross-sectional study and the potential causal relationship between OSAS and high serum Lp-PLA2 levels cannot be concluded. Second, the patients were not followed up prospectively and we did not investigate the effects of treatment on serum Lp-PLA2 levels. In future, multi-center, prospective interventional clinical trials with continuous positive airway pressure treatment are needed to illustrate such phenomenon. In conclusion, the results of our study demonstrated that OSAS with CVD is associated with higher serum Lp-PLA2 levels compared to OSAS without CVD. Lp-PLA2. It was an easy and available test, which might be associated with OSAS severity and playing an important role in predicting CVD in OSAS patients. Declarations of interest: none. Authorship XCY drafted the article or revised it critically for important intellectual content; YFF, MS, SY, LQ, FSR, TY made contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data; GW, YL finally approved the version to be submitted. Fund: This study was supported by the Youth Program of Jiangsu Provincial Natural Scientific Foundation (No. BK20190129), National Scientific Program of Jiangsu Colleges and Universities (No. 19KJB320012), and Scientific and Development Program of Nanjing Medical University (NO. NMUB2018332).
8
Reference [1] M. Sanchez-de-la-Torre, F. Campos-Rodriguez, F. Barbe, Obstructive sleep apnoea and cardiovascular disease, The Lancet. Respiratory medicine 1(1) (2013) 61-72. [2] R.D. McEvoy, N.A. Antic, E. Heeley, et al., CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea, The New England journal of medicine 375(10) (2016) 919-931. [3] A.V. Hernandez, A. Jeon, J. Denegri-Galvan, et al., Use of adaptive servo ventilation therapy as treatment of sleep-disordered breathing and heart failure: a systematic review and meta-analysis, Sleep & breathing = Schlaf & Atmung
(2019).
[4] G. Harada, D. Takeuchi, K. Inai, et al., Prevalence and risk factors of sleep apnoea in adult patients with CHD, Cardiology in the young 29(1) (2019) 71-77. [5] A. Vasheghani-Farahani, F. Kazemnejad, K. Sadeghniiat-Haghighi, et al., Obstructive sleep apnea and severity of coronary artery disease, Caspian journal of internal medicine 9(3) (2018) 276-282. [6] M. Nagayoshi, P.L. Lutsey, D. Benkeser, et al., Association of sleep apnea and sleep duration with peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis (MESA), Atherosclerosis 251 (2016) 467-475. [7] C.D. Turnbull, Intermittent hypoxia, cardiovascular disease and obstructive sleep apnoea, Journal of thoracic disease 10(Suppl 1) (2018) S33-s39. [8] A. Voulgaris, K. Archontogeorgis, N. Papanas, et al., Increased risk for cardiovascular disease in patients with obstructive sleep apnoea syndrome-chronic obstructive pulmonary disease (overlap syndrome), 13(11) (2019) 708-715. [9] C.J. Packard, D.S. O'Reilly, M.J. Caslake, et al., Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group, The New England journal of medicine 343(16) (2000) 1148-1155. [10] C.M. Ballantyne, R.C. Hoogeveen, H. Bang, et al., Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, Circulation 109(7) (2004) 837-842. [11] G. Maiolino, V. Bisogni, G. Rossitto, et al., Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications, World journal of cardiology 7(10) (2015) 609-620. [12] S.K. Ryu, Z. Mallat, J. Benessiano, et al., Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes, Circulation 125(6) (2012) 757-766. 9
[13] F. Yang, L. Ma, L. Zhang, et al., Association between serum lipoprotein-associated phospholipase A2, ischemic modified albumin and acute coronary syndrome: a cross-sectional study, 34(10) (2019) 1608-1614. [14] T.T. Bekci, M. Kayrak, A. Kiyici, et al., The association among lipoprotein-associated phospholipase A2 levels, total antioxidant capacity and arousal in male patients with OSA, International journal of medical sciences 8(5) (2011) 369-376. [15] L. Kheirandish-Gozal, M.F. Philby, Z. Qiao, et al., Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Elevated Lipoprotein-Associated Phospholipase A2 Plasma Activity Levels, Journal of the American Heart Association 6(2) (2017). [16] L.G. Moise, D.S. Marta, A. Rascu, et al., SERUM LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 IN MALES WITH METABOLIC SYNDROME AND OBSTRUCTIVE SLEEP APNEA, Acta endocrinologica (Bucharest, Romania : 2005) 14(1) (2018) 36-42. [17] N.J. Stone, J.G. Robinson, A.H. Lichtenstein, et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation 129(25 Suppl 2) (2014) S1-45. [18] G. Mancia, G. De Backer, A. Dominiczak, et al., 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), Journal of hypertension 25(6) (2007) 1105-1187. [19] J. Shi, J. Piao, B. Liu, et al., Obstructive sleep apnea increases systolic and diastolic blood pressure variability in hypertensive patients, Blood pressure monitoring 22(4) (2017) 208-212. [20] F. Seif, S.R. Patel, H.K. Walia, et al., Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk, Journal of hypertension 32(2) (2014) 267-275. [21] E. Perger, C. Gonzaga-Carvalho, Obstructive Sleep Apnea and Cardiovascular Disease, 199(3) (2019) 377-379. [22] W. Jordan, S. Cohrs, D. Degner, et al., Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome, Journal of neural transmission (Vienna, Austria : 1996) 113(2) (2006) 239-254. [23] T. Yildirim, R. Alp, The role of oxidative stress in the relation between fibromyalgia and 10
obstructive sleep apnea syndrome, European review for medical and pharmacological sciences 21(1) (2017) 20-29. [24] L. Lavie, Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain, Sleep medicine reviews 20 (2015) 27-45. [25] J.C. Charniot, R. Khani-Bittar, J.P. Albertini, et al., Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments, International journal of cardiology 168(1) (2013) 132-138. [26] S. He, B.G. Chousterman, A. Fenn, et al., Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages, Circulation. Heart failure 8(5) (2015) 980-987. [27] A. Zalewski, C. Macphee, Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target, Arteriosclerosis, thrombosis, and vascular biology 25(5) (2005) 923-931. [28] E. Moldoveanu, M. Serban, D.S. Marta, et al., Lipoprotein-associated phospholipase A2 activity in patients with preserved left ventricular ejection fraction, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 16(7) (2011) 587-589. [29] A. Younus, C. Humayun, R. Ahmad, et al., Lipoprotein-associated phospholipase A2 and its relationship with markers of subclinical cardiovascular disease: A systematic review, Journal of clinical lipidology 11(2) (2017) 328-337. [30] I.J. Hatoum, F.B. Hu, J.J. Nelson, et al., Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes, Diabetes 59(5) (2010) 1239-1243. [31] A. Thompson, P. Gao, L. Orfei, et al., Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies, Lancet (London, England) 375(9725) (2010) 1536-1544. [32] M.H. Davidson, M.A. Corson, M.J. Alberts, et al., Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines, The American journal of cardiology 101(12a) (2008) 51f-57f.
11
Table 1 Demographic and clinical characteristics of the study group. Characteristics
OSAS negative (n=31)
Mild OSAS (n=26)
Moderate OSAS (n=41)
Severe OSAS (n=85)
P value
Age (year)
53.94±5.75
53.23±8.96
57.15±6.69
54.60±10.77
0.278
Gender (F, %)
9(29.0)
7(26.9)
14(34.1)
30(26.1)
0.081
BMI (kg/m2)
27.34±2.21
27.42±2.37
28.33±2.57
28.87±2.01
0.067
Cigarette smoking (n,%)
4(12.9)
9(34.6)
13(31.7)
34(40.0)
0.054
Hypertension (n,%)
10(32.3)
6(23.1)
22(53.7)#
56(65.9)*#§
<0.001
Diabetes mellitus (n,%)
6(19.4)
4(15.4)
11(26.8)
25(33.3)
0.235
Dyslipidemia
7(22.6)
6(23.1)
9(22.0)
30(35.3)
0.295
CVD (n,%)
6(19.4)
8(30.8)
14(34.1)
40(47.1) )*#§
0.039
AHI (events/h)
2.47±1.08
10.24±2.69*
22.64±4.63*#
54.17±14.63*#§
<0.001
ODI (events/h)
2.96±1.57
8.47±3.45*
21.40±11.76*#
56.64±23.62*#§
<0.001
MiniSaO2(%)
92.16±3.61
83.73±5.17*
76.09±8.26*#
70.67±10.65*#§
<0.001
Mean SaO2(%)
96.19±1.64
94.31±2.98*
93.83±3.20*#
92.29±4.37*#§
<0.001
TS90 (%)
0(0-1.2)
2.4(0-7.7) *
13.6(1.2-38.8) *#
19.4(3.1-57.8) *#§
<0.001
PSG parameters
Laboratory variables
12
Lp-PLA2 level (ng/ml)
171.83±31.89
174.71±41.41
197.14±48.34*#
220.61±49.37*#
0.025
TG level (mmol/L)
1.62±0.72
1.59±0.67
1.42±0.79
2.24±1.51*#§
<0.001
TC level (mmol/L)
3.87±1.05
4.07±1.55*
4.12±0.85*
4.32±1.26*
0.001
HDL-C level (mmol/L)
1.08±0.19
1.07±0.19
1.11±0.26
1.01±0.25
0.119
LDL-C level (mmol/L)
2.09±0.83
2.37±0.98
2.35±0.61
2.54±0.81
0.064
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase; TG: triglyceride, Tc: total cholesterol; HDL-C, high density-lipoprotein V; LDL-C, low density-lipoprotein cholesterol. OSAS; § p<0.05 versus moderate OSAS.
13
*
P<0.05 versus OSAS negative; # P<0.05 versus mild
Table 2 Comparison of clinical, laboratory and PSG data in OSAS patients with or without CVD Characteristics
OSA with CVD(n=62)
OSA without CVD(n=90)
P value
Age (year)
57.11±8.51
53.63±10.24
0.027
Gender (M,%)
18(29)
33(36.7)
0.327
BMI (kg/m2)
28.67±2.27
28.34±2.83
0.371
AHI (events/h)
41.35±21.42
35.95±21.69
0.032
ODI (events/h)
44.31±29.67
35.17±25.81
0.045
MiniSaO2 (%)
73.01±11.37
75.30±9.73
0.186
Mean SaO2 (%)
92.51±4.95
93.42±3.03
0.165
TS90 (%)
16.3(0-57.8)
17.8(0-54.1)
0.782
Lp-PLA2 level (ng/ml)
226.90±20.77
193.32±18.52
0.033
TG level (mmol/L)
1.95±1.28
1.88±1.19
0.751
TC level (mmol/L)
4.16±1.24
4.26±1.06
0.592
HDL-C level (mmol/L)
1.02±0.24
1.07±0.25
0.328
LDL-C level (mmol/L)
2.37±0.83
2.53±0.77
0.218
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase; TG: triglyceride, Tc: total cholesterol; HDL-C, high density-lipoprotein V; LDL-C, low density-lipoprotein cholesterol.
14
Table 3 Risk factors for CVD in patients with obstructive sleep apnea syndrome Independent variables
Odds ratio
Confidence Interval 95%
P value
Age (year)
1.023
0.892-1.142
0.025
Gender (Male)
0.863
0.654-0.968
0.682
BMI (kg/m2)
1.065
1.021-1.084
0.547
AHI (events/h)
1.004
0.993-1.024
0.026
ODI (events/h)
0.987
0.945-1.125
0.038
Diabetes Mellitus
0.957
0.756-1.034
0.067
MiniSaO2(%)
1.037
0.825-1.125
0.364
Mean SaO2(%)
1.126
0.985-1.234
0.572
TS90 (%)
1.013
0.975-1.038
0.752
Lp-PLA2 level (mg/dl)
1.117
1.002-1.252
0.008
Smoking (n,%)
0.893
0.815-1.032
0.047
Hypertension
0.854
0.678-1.237
0.028
Diabetes mellitus
1.062
0.985-1.241
0.148
Dyslipidemia
0.974
0.753-1.008
0.043
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase.
15
Figure legends Figure 1 Serum Lp-PLA2 in patients with and without cardiovascular disease (CVD) in mild, moderate, severe OSAS patients. *P < 0.05 versus OSAS without CVD.
Figure 2 The ROC curve analysis for Lp-PLA2 in predicting CVD. In OSAS patients, the cut-off value of Lp-PLA2 was 238.09, with a sensitivity of 46.8% and a specificity of 87.8%. The positive predictive value was 72.5%, while the negative predictive value was 70.5%. The AUC was 0.716(95% CI: 0.633–0.799, P<0.001).
16
1. Serum Lp-PLA2 in OSAS patients was significantly higher than that of the negative control. 2. OSAS patients with CVD showed higher Lp-PLA2 compared with those without CVD. 3. There was a strong association between Lp-PLA2 and the severity of OSAS. 4. Lp-PLA2 level was an important predictor for CVD in patients with OSAS.
Declarations of interest: none.
S0954-6111(20)30021-4
DOI:
https://doi.org/10.1016/j.rmed.2020.105881
Reference:
YRMED 105881
To appear in:
Respiratory Medicine
Received Date: 6 December 2019 Revised Date:
20 January 2020
Accepted Date: 26 January 2020
Please cite this article as: Xu C, Yu F, Mao S, Shi Y, Li Q, Fang S, Tan Y, Gu W, Ye L, Lipoproteinassociated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome, Respiratory Medicine (2020), doi: https://doi.org/10.1016/j.rmed.2020.105881. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.
XCY drafted the article or revised it critically for important intellectual content; YFF, MS, SY, LQ, FSR, TY made contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data; GW, YL finally approved the version to be submitted.
Lipoprotein-associated phospholipase A2 predicted cardiovascular disease in obstructive sleep apnea syndrome Chenyu Xu#, Fenfang Yu#, Shan Mao, Ying Shi, Qian Li, Surong Fang, Yan Tan, Wei Gu*, Liang Ye* Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China #
These authors contributed equally to this work.
Correspondence to: Liang Ye, Department of Respiration, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Qinhuai District, Nanjing 210006, China. Tel.: +86-25-87726230; Email: [email protected] Wei Gu, Department of Respiration, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Qinhuai District, Nanjing 210006, China. Tel.: +86-25-87726231; Email: [email protected]
1
Abstract Background: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease (CVD). As a new inflammatory biomarker of CVD, rare attention has been paid to the roles of lipoprotein-associated phospholipase (Lp-PLA2) in OSAS studies. In this study, we aimed to investigate the correlation between Lp-PLA2 and concomitant CVD in OSAS patients. Methods: In this prospective study, 152 OSAS patients were further divided into mild, moderate, and severe OSAS subgroups. They presented heart failure, coronary artery disease, or arrhythmia were confirmed with CVD. Thirty-one subjects without OSAS were recruited for the control group. The relationship between Lp-PLA2 and concomitant CVD in OSAS patients was analyzed. Results: Serum Lp-PLA2 values were significantly higher in the severe and moderate OSAS group compared with mild OSAS and OSAS negative groups (P=0.025). Significant increase was noticed in serum Lp-PLA2 levels in CVD patients compared with those without in severe-moderate-mild OSAS (P<0.05). In logistic regression analysis, the level of Lp-PLA2 was proved as a significant independent predictor for CVD (OR =1.117, P=0.008). The ROC analysis indicated that the best cut-off value of Lp-PLA2 for predicting CVD in OSAS patients was 238.09 ng/ml. The positive and negative predictive values were 72.5% and 70.5%, respectively. The sensitivity was 46.8% and the specificity was 87.8%. Conclusions: Lp-PLA2 might be associated with the severity of OSAS and the occurrence of CVD in OSAS patients. Lp-PLA2 is expected to be a promising biomarker candidate in predicting CVD in patients with OSAS due to test convenience. Keywords:
Obstructive
sleep
apnea
syndrome
(OSAS);
lipoprotein-associated phospholipase (Lp-PLA2); biomarker
2
cardiovascular
disease
(CVD);
Introduction Obstructive sleep apnea syndrome (OSAS), a common disorder featured by repetitive episodes of nocturnal breathing cessation, is reported to significantly increase the risk of cardiovascular diseases (CVD) including hypertension[1, 2], heart failure[3, 4], arrhythmia, coronary artery disease (CAD)[5, 6]. OSAS patients usually present chronic intermittent hypoxemia and sleep fragmentation, which may trigger diverse syndromes by modulating various signaling pathways[7]. To our best knowledge, patients with sleep apnea frequently show sympathetic activation, oxidative stress, and metabolic dysregulation, suggesting a possible link between OSAS and CVD [8]. Recently, much attention has been paid to lipoprotein-associated phospholipase A2 (Lp-PLA2) serving as an independent risk factor for CVD [9, 10]. Lp-PLA2 is an inflammatory enzyme produced by monocytes, macrophages and T lymphocytes, which is up-regulated in atherosclerotic plaques[11]. It has been proved to show high specificity for vascular inflammation unlike the other systemic inflammation. Lp-PLA2 elevation or activation could predict both primary and recurrent coronary or cardiovascular events in the general population[12, 13]. To date, a few studies have investigated the roles of Lp-PLA2 in OSAS patients[14-16]. However, little is known about the association between Lp-PLA2 and CVD occurrence in OSAS patients. This study was designed to evaluate the correlation between serum Lp-PLA2 levels and cardiovascular events in OSAS patients. In addition, we investigated the efficiency of Lp-PLA2 as a marker for predicting CVD in OSAS patients. Material and methods Patients In this study, we included patients presented to the Sleep Disorders Center at Nanjing First Hospital due to sleep-disordered breathing problems from September 2014 to January 2019. All subjects underwent overnight polysomnography (PSG) and were recruited after signing an institutional ethics committee-approved consent form. The average apneas and hypopneas per hour of sleep was defined as the apnea-hypopnea index (AHI). The diagnosis and severity of OSAS was based on the following criteria recommended by the American Academy of Sleep Medicine: OSAS negative group (AHI < 5), mild OSAS group (5 ≤ AHI < 15), moderate OSAS group (15 ≥ AHI < 30) and severe OSAS group (AHI ≥ 30). The exclusion criteria were as follows: those with central sleep apnea syndrome, upper airway resistant syndrome, and narcolepsy or movement disorder; those received 3
treatment for OSAS, CVD, hypoxemic lung disease, hematologic disease, liver or kidney disease, chronic alcoholism, malignancy, pregnancy, acute and/or chronic infection, or autoimmune disease previously. Demographic characteristics, sleep, and medical history, including cardiovascular and metabolic diseases, medication, and habits were obtained based on a standardized questionnaire. CVD was defined according to the presence of heart failure, coronary artery disease or arrhythmia. The demographic characteristics [e.g. (body mass index)] and laboratory evaluation were performed including routine blood tests (e.g. fasting glucose, liver enzymes, lipid profile), respiratory function tests, and electrocardiogram. Each patient signed the informed consent. The study protocols were approved by the Ethics Committee of Nanjing First Hospital, Nanjing Medical University. A BMI of >30 kg/m2 was defined as obese. Hyperlipidemia was defined as follows: serum low-density lipoprotein cholesterol (HDL-c) of ≥4.1 mmol/L; or total cholesterol (TC) of >6.2mmol/L; or triglyceride (TG) of ≥2.3 mmol/L; or high-density lipoprotein cholesterol (HDL-c) of <1.0 mmol/L[17]. Blood pressure was measured at the non-dominant arm in the morning of the procedure after a 5 min interval. Hypertension was defined based on the standards proposed by 2007 European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) task force for the management of arterial hypertension guidelines[18]. PSG evaluation The presence or absence of OSAS was based on the standard polysomnography System (Philips Respironics, Murrayvile, PA) with Alice Sleepware Software. PSG data were analyzed manually by a respiratory physiologist using the Irish Sleep Society/AASM guidelines. Obstructive apnea was defined as a drop in airflow to ≤ 90% of baseline for ≥ 10s as recorded with the oronasal sensor. Hypopnea was defined as a drop in airflow ≥ 30% from baseline as recorded with the nasal cannula for ≥ 10s accompanied by ≥ 3% oxygen desaturation or an arousal. PSG parameters including the oxygen desaturation index (ODI), minimal arterial oxygen saturation (MiniSaO2), mean O2 saturation (SaO2), time spent below 90% oxygen saturation (TS90%) and arousal index were also recorded using standard PSG System (Philips Respironics, Murrayvile, PA). Laboratory analysis Fasting blood samples were collected in the morning after PSG monitoring. Serum samples were obtained from patients using a serum separator tube and allowed to clot for two hours at room temperature before centrifugation for 20 min at 1000 g. Then the samples were frozen and stored at 4
-80°C until analysis. Serum Lp-PLA2 levels were measured using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instruction (Kangerke Biotech, Tianjin, China). Levels of lipids including TC, HDL-c, calculated LDL-c, and TG were assessed with a Flex reagent cartridge (Date Behring, Newark, DE). Statistical analysis The
distribution
of
continuous
variables
for
normality
was
tested
with
One-Sample
Kolmogorov-Smirnov test. The data were presented as mean ± standard deviation (SD), or median and interquartile ranges. Categorical variables were presented as frequencies and percentages. The normal distribution of continuous variables was evaluated using the Shapiro-Wilks test. According to continuous variables with normal distribution or not, the continuous variables among the groups were compared using one-way analysis of variance (ANOVA) or Kruskal-Wallis test. In one-way ANOVA for post hoc multiple comparison, Student-Newman-Keuls (SNK) test was used. Nemenyi test was performed for the multiple comparisons in Kruskal-Wallis test. Based on continuous variables with normal distribution or not, continuous variables between OSAS without CVD and OSAS with CVD groups were compared using two independent sample t tests or Mann-Whitney U tests. Continuous variables were expressed as mean (standard deviation) for the one-way ANOVA or two independent sample t-tests. For the Kruskal-Wallis test and Mann-Whitney U test, continuous variables were expressed as median (interquartile range). Chi square test was conducted for the analysis categorical variables. The independent predictors related to CVD in OSAS was determined using multiple logistic regression analysis. The predictive validity and optimal Lp-PLA2 cut-off value were estimated using the receiver-operating characteristic (ROC) curve. Data were analyzed using SPSS 18.0 software (IBM, Chicago, IL, USA). P value of <0.05 was considered statistically significant. Results A total of 183 patients met the selection criteria were included in the analysis. Demographic and biochemical data were presented in Table 1. Among these cases, 152 participants were diagnosed as OSAS, while 31 patients with an AHI of < 5 served as the OSAS negative group. As expected, there were statistical differences between the desaturation index, minimum oxygen saturation and mean oxygen saturation between these two groups (P<0.001, Table 1). The prevalence of CVD in the patients of severe OSAS group was significantly higher than that of the moderate and mild OSAS groups, as well as the OSAS negative group (P=0.039, Table 1). Serum 5
TG levels in severe OSAS group were significantly higher than the OSAS negative group, mild and moderate OSAS groups (P<0.001; Table 1). TC levels of OSAS patients were significantly higher than non-OSAS patients (P=0.001; Table 1). Meanwhile, Lp-PLA2 values were significantly higher in the severe and moderate OSAS group compared with mild OSAS and OSAS negative groups (P=0.025, Table 1). In Table 2, we further compared the differences of the clinical, laboratory and PSG data between OSAS patients with (n=62) and without CVD (n=90). OSAS patients with CVD showed higher AHI and ODI (P<0.05). Meanwhile, the Lp-PLA2 values of OSA patients with CVD were significantly higher than those without CVD (P=0.033, Table 2). Moreover, based on the grouping given by disease severity, our data showed that serum Lp-PLA2 levels were significantly higher in patients with CVD compared with those without in mild, moderate and severe OSAS groups (Fig. 1, P < 0.05). Finally, potential determinants for the CVD were investigated. In the logistic regression analysis for the risk factors of CVD among OSAS patients, Lp-PLA2 was determined as an independent predictor of CVD (OR =1.117, 95% CI: 1.002–1.252, P=0.008, Table 3). For the prediction of CVD in OSAS patients, the ROC curve analysis performed the cut-off value of Lp-PLA2 (>238.09) showed a sensitivity of 46.8% and a specificity of 87.8%. The positive predictive value and negative predictive value was 72.5% and 70.5%, respectively. The area under the curve value (AUC) was 0.716 (95% CI: 0.633–0.799, P<0.001; Figure 2). Discussion There were two novel findings in this study. First, serum Lp-PLA2 levels were significantly higher in a proportional manner with the deterioration of OSAS conditions. Second, Lp-PLA2 was proved as an independent predictor for OSAS cases with CVD. Cardiovascular complications, including hypertension, coronary artery disease, cardiac failure, cardiac arrhythmia, ventricular dysfunction, and pulmonary hypertension[19, 20], are the most serious complications of the patients with OSAS[21]. Nowadays, the mechanisms of impairment in myocardial contraction and relaxation among OSAS patients are still not well defined. Nevertheless, OSAS has been reported to be associated with the cardiac risks due to the derangement of the relation between myocardial oxygen demand and supply as a result of hypoxia, hypercapnia, increased sympathetic activation during apnea, and oxygen desaturation periods associated with apnea [22]. Intermittent episodes of hypoxia as a result of transient cessation of breathing during sleep were major physiologic 6
characteristics of OSAS and were resemble ischemia–reperfusion injury. Intermittent nocturnal hypoxemia induced the production of oxygen-free radicals, causing a state of low-grade circulation and local inflammation[23, 24]. These results demonstrated that inflammation and oxidative stress were important factors in the pathogenesis of cardiovascular complications in OSAS cases. Lp-PLA2 is a serine lipase mainly produced by activated monocytes and macrophages[25]. In the bloodstream, 1/3 of Lp-PLA2 circulates bound to HDLs and the other 2/3 to LDLs, with protein B100 serving as the mediator [26]. Lp-PLA2 entered the vessel wall and catalyzed the hydrolysis of the phospholipids
on
the
surface
of
the
LDLs,
which
then
resulted
in
the
release
of
lysophosphatidylcholine and oxidized fatty acids. These mediators triggered the inflammatory cascade, induced the chemotaxis of leucocytes into the sub-intimal space of the arterial wall and converted them into foam cells. As a consequence, Lp-PLA2 enhanced the growth and the instability of the lipid core of the atherosclerotic plaques, which consequently led to acute cardiovascular events [27-29]. Several studies have confirmed the roles of Lp-PLA2 as a predictor of CVD morbidity and mortality in apparently healthy populations, in diabetic and dysmetabolic patients and those with cardiac disease[30, 31]. Based on this evidence, the guidelines of three major heart international societies, the American College of Cardiology, the American Heart Association and the European Society of Cardiology, have included Lp-PLA2 activity measurement in the risk stratification of asymptomatic patients in order to optimize the lipid lowering therapy[32]. To date, few studies have investigated the roles of Lp-PLA2 in OSAS. In a previous study, Moise et al. found that serum Lp-PLA2 levels were higher in OSAS patients with metabolic syndrome than those without [16]. Besides, Barcelo et al evaluated the antioxidant capacity in male patients with OSAS, which demonstrated decrease of total antioxidant capacity and increase of Lp-PLA2 values among these patients [14]. This implicated oxidative stress as a contributing factor in the development of cardiac complications in cases with OSAS. In our study, the levels of Lp-PLA2 were higher in those with severe OSAS. This might explain the higher incidence of cardiovascular complications in cases with severe OSAS. In fact, the most important observation of the study was that we proved significantly higher levels of Lp-PLA2 in cases with CVD compared to those without. The Lp-PLA2 level was revealed to be an independent predictor for CVD in cases with OSAS. In addition, we herein found that Lp-PLA2 of 238.09 ng/ml could predict CVD occurrence in patients with OSAS, with the sensitivity of 46.8%, a specificity of 87.8%, and positive and negative predictive values of 72.5% and 7
70.5%, respectively. Our study yielded important outcomes in that it was conducted in a relatively larger patient population and emphasized the importance of Lp-PLA2 in the prediction of CVD in OSAS cases. However, there are some limitations of our study that we have to mention. First, this is a cross-sectional study and the potential causal relationship between OSAS and high serum Lp-PLA2 levels cannot be concluded. Second, the patients were not followed up prospectively and we did not investigate the effects of treatment on serum Lp-PLA2 levels. In future, multi-center, prospective interventional clinical trials with continuous positive airway pressure treatment are needed to illustrate such phenomenon. In conclusion, the results of our study demonstrated that OSAS with CVD is associated with higher serum Lp-PLA2 levels compared to OSAS without CVD. Lp-PLA2. It was an easy and available test, which might be associated with OSAS severity and playing an important role in predicting CVD in OSAS patients. Declarations of interest: none. Authorship XCY drafted the article or revised it critically for important intellectual content; YFF, MS, SY, LQ, FSR, TY made contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data; GW, YL finally approved the version to be submitted. Fund: This study was supported by the Youth Program of Jiangsu Provincial Natural Scientific Foundation (No. BK20190129), National Scientific Program of Jiangsu Colleges and Universities (No. 19KJB320012), and Scientific and Development Program of Nanjing Medical University (NO. NMUB2018332).
8
Reference [1] M. Sanchez-de-la-Torre, F. Campos-Rodriguez, F. Barbe, Obstructive sleep apnoea and cardiovascular disease, The Lancet. Respiratory medicine 1(1) (2013) 61-72. [2] R.D. McEvoy, N.A. Antic, E. Heeley, et al., CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea, The New England journal of medicine 375(10) (2016) 919-931. [3] A.V. Hernandez, A. Jeon, J. Denegri-Galvan, et al., Use of adaptive servo ventilation therapy as treatment of sleep-disordered breathing and heart failure: a systematic review and meta-analysis, Sleep & breathing = Schlaf & Atmung
(2019).
[4] G. Harada, D. Takeuchi, K. Inai, et al., Prevalence and risk factors of sleep apnoea in adult patients with CHD, Cardiology in the young 29(1) (2019) 71-77. [5] A. Vasheghani-Farahani, F. Kazemnejad, K. Sadeghniiat-Haghighi, et al., Obstructive sleep apnea and severity of coronary artery disease, Caspian journal of internal medicine 9(3) (2018) 276-282. [6] M. Nagayoshi, P.L. Lutsey, D. Benkeser, et al., Association of sleep apnea and sleep duration with peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis (MESA), Atherosclerosis 251 (2016) 467-475. [7] C.D. Turnbull, Intermittent hypoxia, cardiovascular disease and obstructive sleep apnoea, Journal of thoracic disease 10(Suppl 1) (2018) S33-s39. [8] A. Voulgaris, K. Archontogeorgis, N. Papanas, et al., Increased risk for cardiovascular disease in patients with obstructive sleep apnoea syndrome-chronic obstructive pulmonary disease (overlap syndrome), 13(11) (2019) 708-715. [9] C.J. Packard, D.S. O'Reilly, M.J. Caslake, et al., Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group, The New England journal of medicine 343(16) (2000) 1148-1155. [10] C.M. Ballantyne, R.C. Hoogeveen, H. Bang, et al., Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, Circulation 109(7) (2004) 837-842. [11] G. Maiolino, V. Bisogni, G. Rossitto, et al., Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications, World journal of cardiology 7(10) (2015) 609-620. [12] S.K. Ryu, Z. Mallat, J. Benessiano, et al., Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes, Circulation 125(6) (2012) 757-766. 9
[13] F. Yang, L. Ma, L. Zhang, et al., Association between serum lipoprotein-associated phospholipase A2, ischemic modified albumin and acute coronary syndrome: a cross-sectional study, 34(10) (2019) 1608-1614. [14] T.T. Bekci, M. Kayrak, A. Kiyici, et al., The association among lipoprotein-associated phospholipase A2 levels, total antioxidant capacity and arousal in male patients with OSA, International journal of medical sciences 8(5) (2011) 369-376. [15] L. Kheirandish-Gozal, M.F. Philby, Z. Qiao, et al., Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Elevated Lipoprotein-Associated Phospholipase A2 Plasma Activity Levels, Journal of the American Heart Association 6(2) (2017). [16] L.G. Moise, D.S. Marta, A. Rascu, et al., SERUM LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 IN MALES WITH METABOLIC SYNDROME AND OBSTRUCTIVE SLEEP APNEA, Acta endocrinologica (Bucharest, Romania : 2005) 14(1) (2018) 36-42. [17] N.J. Stone, J.G. Robinson, A.H. Lichtenstein, et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Circulation 129(25 Suppl 2) (2014) S1-45. [18] G. Mancia, G. De Backer, A. Dominiczak, et al., 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), Journal of hypertension 25(6) (2007) 1105-1187. [19] J. Shi, J. Piao, B. Liu, et al., Obstructive sleep apnea increases systolic and diastolic blood pressure variability in hypertensive patients, Blood pressure monitoring 22(4) (2017) 208-212. [20] F. Seif, S.R. Patel, H.K. Walia, et al., Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk, Journal of hypertension 32(2) (2014) 267-275. [21] E. Perger, C. Gonzaga-Carvalho, Obstructive Sleep Apnea and Cardiovascular Disease, 199(3) (2019) 377-379. [22] W. Jordan, S. Cohrs, D. Degner, et al., Evaluation of oxidative stress measurements in obstructive sleep apnea syndrome, Journal of neural transmission (Vienna, Austria : 1996) 113(2) (2006) 239-254. [23] T. Yildirim, R. Alp, The role of oxidative stress in the relation between fibromyalgia and 10
obstructive sleep apnea syndrome, European review for medical and pharmacological sciences 21(1) (2017) 20-29. [24] L. Lavie, Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain, Sleep medicine reviews 20 (2015) 27-45. [25] J.C. Charniot, R. Khani-Bittar, J.P. Albertini, et al., Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments, International journal of cardiology 168(1) (2013) 132-138. [26] S. He, B.G. Chousterman, A. Fenn, et al., Lp-PLA2 Antagonizes Left Ventricular Healing After Myocardial Infarction by Impairing the Appearance of Reparative Macrophages, Circulation. Heart failure 8(5) (2015) 980-987. [27] A. Zalewski, C. Macphee, Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target, Arteriosclerosis, thrombosis, and vascular biology 25(5) (2005) 923-931. [28] E. Moldoveanu, M. Serban, D.S. Marta, et al., Lipoprotein-associated phospholipase A2 activity in patients with preserved left ventricular ejection fraction, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 16(7) (2011) 587-589. [29] A. Younus, C. Humayun, R. Ahmad, et al., Lipoprotein-associated phospholipase A2 and its relationship with markers of subclinical cardiovascular disease: A systematic review, Journal of clinical lipidology 11(2) (2017) 328-337. [30] I.J. Hatoum, F.B. Hu, J.J. Nelson, et al., Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes, Diabetes 59(5) (2010) 1239-1243. [31] A. Thompson, P. Gao, L. Orfei, et al., Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies, Lancet (London, England) 375(9725) (2010) 1536-1544. [32] M.H. Davidson, M.A. Corson, M.J. Alberts, et al., Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines, The American journal of cardiology 101(12a) (2008) 51f-57f.
11
Table 1 Demographic and clinical characteristics of the study group. Characteristics
OSAS negative (n=31)
Mild OSAS (n=26)
Moderate OSAS (n=41)
Severe OSAS (n=85)
P value
Age (year)
53.94±5.75
53.23±8.96
57.15±6.69
54.60±10.77
0.278
Gender (F, %)
9(29.0)
7(26.9)
14(34.1)
30(26.1)
0.081
BMI (kg/m2)
27.34±2.21
27.42±2.37
28.33±2.57
28.87±2.01
0.067
Cigarette smoking (n,%)
4(12.9)
9(34.6)
13(31.7)
34(40.0)
0.054
Hypertension (n,%)
10(32.3)
6(23.1)
22(53.7)#
56(65.9)*#§
<0.001
Diabetes mellitus (n,%)
6(19.4)
4(15.4)
11(26.8)
25(33.3)
0.235
Dyslipidemia
7(22.6)
6(23.1)
9(22.0)
30(35.3)
0.295
CVD (n,%)
6(19.4)
8(30.8)
14(34.1)
40(47.1) )*#§
0.039
AHI (events/h)
2.47±1.08
10.24±2.69*
22.64±4.63*#
54.17±14.63*#§
<0.001
ODI (events/h)
2.96±1.57
8.47±3.45*
21.40±11.76*#
56.64±23.62*#§
<0.001
MiniSaO2(%)
92.16±3.61
83.73±5.17*
76.09±8.26*#
70.67±10.65*#§
<0.001
Mean SaO2(%)
96.19±1.64
94.31±2.98*
93.83±3.20*#
92.29±4.37*#§
<0.001
TS90 (%)
0(0-1.2)
2.4(0-7.7) *
13.6(1.2-38.8) *#
19.4(3.1-57.8) *#§
<0.001
PSG parameters
Laboratory variables
12
Lp-PLA2 level (ng/ml)
171.83±31.89
174.71±41.41
197.14±48.34*#
220.61±49.37*#
0.025
TG level (mmol/L)
1.62±0.72
1.59±0.67
1.42±0.79
2.24±1.51*#§
<0.001
TC level (mmol/L)
3.87±1.05
4.07±1.55*
4.12±0.85*
4.32±1.26*
0.001
HDL-C level (mmol/L)
1.08±0.19
1.07±0.19
1.11±0.26
1.01±0.25
0.119
LDL-C level (mmol/L)
2.09±0.83
2.37±0.98
2.35±0.61
2.54±0.81
0.064
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase; TG: triglyceride, Tc: total cholesterol; HDL-C, high density-lipoprotein V; LDL-C, low density-lipoprotein cholesterol. OSAS; § p<0.05 versus moderate OSAS.
13
*
P<0.05 versus OSAS negative; # P<0.05 versus mild
Table 2 Comparison of clinical, laboratory and PSG data in OSAS patients with or without CVD Characteristics
OSA with CVD(n=62)
OSA without CVD(n=90)
P value
Age (year)
57.11±8.51
53.63±10.24
0.027
Gender (M,%)
18(29)
33(36.7)
0.327
BMI (kg/m2)
28.67±2.27
28.34±2.83
0.371
AHI (events/h)
41.35±21.42
35.95±21.69
0.032
ODI (events/h)
44.31±29.67
35.17±25.81
0.045
MiniSaO2 (%)
73.01±11.37
75.30±9.73
0.186
Mean SaO2 (%)
92.51±4.95
93.42±3.03
0.165
TS90 (%)
16.3(0-57.8)
17.8(0-54.1)
0.782
Lp-PLA2 level (ng/ml)
226.90±20.77
193.32±18.52
0.033
TG level (mmol/L)
1.95±1.28
1.88±1.19
0.751
TC level (mmol/L)
4.16±1.24
4.26±1.06
0.592
HDL-C level (mmol/L)
1.02±0.24
1.07±0.25
0.328
LDL-C level (mmol/L)
2.37±0.83
2.53±0.77
0.218
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase; TG: triglyceride, Tc: total cholesterol; HDL-C, high density-lipoprotein V; LDL-C, low density-lipoprotein cholesterol.
14
Table 3 Risk factors for CVD in patients with obstructive sleep apnea syndrome Independent variables
Odds ratio
Confidence Interval 95%
P value
Age (year)
1.023
0.892-1.142
0.025
Gender (Male)
0.863
0.654-0.968
0.682
BMI (kg/m2)
1.065
1.021-1.084
0.547
AHI (events/h)
1.004
0.993-1.024
0.026
ODI (events/h)
0.987
0.945-1.125
0.038
Diabetes Mellitus
0.957
0.756-1.034
0.067
MiniSaO2(%)
1.037
0.825-1.125
0.364
Mean SaO2(%)
1.126
0.985-1.234
0.572
TS90 (%)
1.013
0.975-1.038
0.752
Lp-PLA2 level (mg/dl)
1.117
1.002-1.252
0.008
Smoking (n,%)
0.893
0.815-1.032
0.047
Hypertension
0.854
0.678-1.237
0.028
Diabetes mellitus
1.062
0.985-1.241
0.148
Dyslipidemia
0.974
0.753-1.008
0.043
Abbreviations: OSAS, obstructive sleep apnea syndrome; BMI, body mass index; CVD, cardiovascular disease; AHI, apnea-hypopnea index; ODI, oxygen desaturation index; MiniSaO2, minimal arterial oxygen saturation; Mean SaO2, mean O2 saturation; TS90%, time spent below 90% oxygen saturation; Lp-PLA2, lipoprotein-associated phospholipase.
15
Figure legends Figure 1 Serum Lp-PLA2 in patients with and without cardiovascular disease (CVD) in mild, moderate, severe OSAS patients. *P < 0.05 versus OSAS without CVD.
Figure 2 The ROC curve analysis for Lp-PLA2 in predicting CVD. In OSAS patients, the cut-off value of Lp-PLA2 was 238.09, with a sensitivity of 46.8% and a specificity of 87.8%. The positive predictive value was 72.5%, while the negative predictive value was 70.5%. The AUC was 0.716(95% CI: 0.633–0.799, P<0.001).
16
1. Serum Lp-PLA2 in OSAS patients was significantly higher than that of the negative control. 2. OSAS patients with CVD showed higher Lp-PLA2 compared with those without CVD. 3. There was a strong association between Lp-PLA2 and the severity of OSAS. 4. Lp-PLA2 level was an important predictor for CVD in patients with OSAS.
Declarations of interest: none.