Bouloukaki I, Mermigkis C, Kallergis EM, Moniaki V, Mauroudi E, Schiza SE. Obstructive sleep apnea syndrome and cardiovascular disease: The influence of C-reactive protein. World J Exp Med 2015; 5(2): 77-83
Corresponding Author of This Article
Sophia E Schiza, MD, PhD, Assistant Professor of Respiratory Medicine, Sleep Disorders Center, Department of Thoracic Medicine, University General Hospital, Medical School of the University of Crete, Rio, 71110 Heraklion, Crete, Greece. firstname.lastname@example.org
Checklist of Responsibilities for the Scientific Editor of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Obstructive sleep apnea syndrome and cardiovascular disease: The influence of C-reactive protein
Izolde Bouloukaki, Charalampos Mermigkis, Eleftherios M Kallergis, Violeta Moniaki, Eleni Mauroudi, Sophia E Schiza
Izolde Bouloukaki, Charalampos Mermigkis, Eleftherios M Kallergis, Violeta Moniaki, Eleni Mauroudi, Sophia E Schiza, Sleep Disorders Center, Department of Thoracic Medicine, University General Hospital, Medical School of the University of Crete, 71110 Heraklion, Crete, Greece
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed to conception and design of the study, acquisition of data, or analysis and interpretation of data, drafted the article or making critical revisions related to important intellectual content of the manuscript and approved of the final version of the article to be published.
Conflict-of-interest: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sophia E Schiza, MD, PhD, Assistant Professor of Respiratory Medicine, Sleep Disorders Center, Department of Thoracic Medicine, University General Hospital, Medical School of the University of Crete, Rio, 71110 Heraklion, Crete, Greece. email@example.com
Telephone: +30-281-0394824 Fax: +30-281-0394670
Received: October 20, 2014 Peer-review started: October 20, 2014 First decision: November 27, 2014 Revised: March 2, 2015 Accepted: March 18, 2015 Article in press: March 20, 2015 Published online: May 20, 2015
Obstructive sleep apnea syndrome (OSAS) is a common medical condition, associated with atherosclerosis and cardiovascular disease (CVD). The underlying pathophysiologic mechanisms of this association have not been completely understood and may be multifactorial in origin. A number of studies suggest that inflammatory processes have emerged critical in the pathogenesis of CVD in OSAS. A range of circulating inflammatory molecules has been identified and measured, with a view to assess inflammation and predict vascular damage risk, such as plasma cytokines, adhesion molecules, and C-reactive protein (CRP). CRP is a relevant marker worthy of further study, because not only is elevated in patients with OSAS, but also is rapidly becoming a risk factor for cardiac disease. Furthermore, in selected OSAS patients, aggressive treatment of the disorder may lead to retarding or even improvement of CVD progression. However, still there is a debate on the true correlation between CRP and OSAS, as well as the clinical effect of any reduction after OSAS treatment. Further research is required to define those OSAS patients who will have a considerable reduction with treatment, as well as to understand the significance of the interaction between cardiovascular risk factor and CRP reduction in patients with OSAS.
Core tip: Obstructive sleep apnea syndrome (OSAS) is a common medical condition, associated with atherosclerosis and cardiovascular disease (CVD). A number of studies suggest that inflammatory processes have emerged critical in the pathogenesis of CVD in OSAS. C-reactive protein (CRP) has been the most studied inflammatory protein to date and a frequently used marker to predict the occurrence of CVDs. Unfortunately, the question still remains if CRP is truly related to OSAS, as well as the clinical effect of any reduction after treatment of OSAS.
Citation: Bouloukaki I, Mermigkis C, Kallergis EM, Moniaki V, Mauroudi E, Schiza SE. Obstructive sleep apnea syndrome and cardiovascular disease: The influence of C-reactive protein. World J Exp Med 2015; 5(2): 77-83
Obstructive sleep apnea syndrome (OSAS) is a common medical condition, characterized by repetitive episodes of upper airway obstruction that occur during sleep. These intermittent episodes are leading to disruption of normal ventilation and sleep architecture and ultimately through a range of pathophysiological mechanisms in cardiovascular disease (CVD). Indeed OSAS, when not correctly treated, has been associated with higher fatal and nonfatal cardiovascular events. It is worth noting that the cardiovascular consequences of OSAS may develop even in the absence of the traditional cardiovascular risk factors. Therefore, clinicians should be aware that OSAS has emerged as an independent risk factor for CVD.
Several mechanisms are involved in the association between OSAS and CVD, such as enhanced sympathetic activity, oxidative stress, systemic inflammation, and endothelial dysfunction which promote atherogenesis. Atherosclerosis could be one of the mechanisms connecting OSAS to CVD. There is growing evidence that the underlying inflammatory process plays a crucial role in all stages of the atherosclerotic disease process, with established CVD seen as the end of a long process of inflammation-mediated atherosclerosis[5,6]. Since inflammation has a key role in the development of CVD it is a common sense to assume that OSAS may contribute to CVD through an inflammatory mechanism. Therefore, evaluation of circulating biomarkers of inflammation could be a useful risk assessment tool for identifying patients with cardiovascular events.
A range of circulating inflammatory molecules has been identified and measured, with a view to assess inflammation and predict vascular damage risk, such as plasma cytokines, adhesion molecules, and C-reactive protein (CRP). Of these markers, CRP, an acute phase reactant synthesized in the liver, is one of the most widely investigated biomarkers of low-grade inflammation in CVD. A number of studies have demonstrated that CRP is a significant risk factor for atherosclerosis and higher CRP levels, even in the high normal range (0.2 to 1.5 mg/dL) are associated with high cardiovascular morbidity and mortality in individuals with and without known CVD[7-10]. In patients with OSAS elevated levels of inflammatory markers, such as CRP, have been found; however there is a debate on the true relationship between CRP and OSAS.
This short review will try to highlight the most clinically relevant updates on the relationship between OSAS and CRP and how this relationship could contribute to CVD. It cannot judge all newly-available information, but information from the literature considered to be of sufficient primary care interest has been summarized.
OSAS AND INFLAMMATORY ACTIVATION
OSAS is characterized by cyclical episodes of hypoxia and reoxygenation that can provoke oxidative stress due to reactive oxygen species production and inflammatory mediators activation. In addition, these alterations can turn on nuclear transcriptional factors, including nuclear factor-B, which induce production of inflammatory mediators, intracellular and vascular cell adhesion molecules. All the above could facilitate vascular endothelial damage and atherogenesis[13-15]. In this way, intermittent hypoxia may lead to atherosclerosis and, ultimately, the cardiovascular consequences of OSAS.
A range of inflammatory molecules has been localized to the atherosclerotic plaque[16-18]. Among them, CRP and interleukin-6 (IL-6) are the most widely studied in CVD.
OSAS AND CRP
Several authors have studied the relationship between apnea-hypopnea index (AHI) and CRP levels in OSAS patients, but the results are contradictory (Table 1). Factors such as sample size, statistical methodology and study design could be responsible for this disparity. Most of the studies to date[19-22] presented elevated CRP levels in OSAS patients; however the role of obesity and sleep duration in this CRP elevation has been questioned by other studies[20,23]. Therefore, as the role of CRP as a risk factor in OSAS is open to discussion, one could speculate that CRP’s value as a special marker of OSAS-related cardiovascular risk is attenuated. However, a recent meta-analysis has shown that patients with OSAS had a statistically significant higher level of CRP and this effect was positively influenced by OSAS severity.
Table 1 Previous studies on the relationship between obstructive sleep apnea syndrome, C-reactive protein and other inflammatory markers.
AHI was associated with CRP, IL-6, fibrinogen, ICAM, and P-selectin but not with TNF-α, TNF-R2, CD40-ligand, or MCP-1 levels The associations were substantially attenuated, and remained statistically significant only for IL-6, after adjustment for BMI
The levels of CRP, IL-6 and lysozyme were significantly higher in subjects with AHI > 15 compared with subjects with lower AHI In multiple linear regressions adjusting for age, waist circumference and smoking, independent correlations between ODI and inflammation were found for IL-6 and TNF-α
The serum CRP levels were significantly higher in the OSA group than in the control group In multiple regression analysis, elevated hs-CRP levels were associated with AHI which was independent of obesity
A strong association was found between degree of SDB and serum levels of CRP, with or without adjustment for age and several measures of adiposity. Moreover, an independent association between serum CRP levels and nocturnal hypoxia was also observed, whereas no association was noted with parameters of sleep architecture
CRP and IL-6 and production of IL-6 were significantly higher in patients with OSAS than in obese control subjects. The severity of OSAS and BMI were independently related to levels of CRP, whereas BMI and apnea-related nocturnal hypoxia were independently related to levels of IL-6 in patients with OSAS
Serum CRP, TF, MCP-1 and Hsp-70 levels were significantly higher in OSAS compared with control subjects However, the best correlation with serum CRP levels was BMI and it was the most significant determinant for CRP
Cardiovascular complications represent a considerable part of OSAS complications. OSAS is an independent risk factor for CVDs, such as hypertension, arrhythmias, pulmonary hypertension, coronary artery disease, congestive cardiac failure and cerebrovascular events[25,26].
Although a matter of debate, the role of OSAS in the pathogenesis of hypertension is strongly suggested[11,27], involving markers or pathways indicative of systemic inflammation, such as CRP. Furthermore, in animal studies intermittent hypoxia has been shown to produce hypertension[28,29].
Cardiac arrhythmias appear to be a common in OSAS patients; still their true prevalence remains unknown. The severity of OSAS, as shown in most studies, is independently associated with elevated markers of systemic inflammation, including CRP. CRP is directly associated with an increased atrial fibrillation burden and strongly and independently associated with occurrence of heart failure[31,32]. Furthermore, serum levels of CRP were significantly increased in patients with OSAS and an acute cardiovascular event. In patients with coronary artery disease on current optimal medications for secondary cardiovascular risk reduction, highly sensitive CRP was significantly correlated with the severity of OSAS, suggesting that OSAS could activate vascular inflammation in these patients despite current best practice medications. Moreover, OSAS is independently associated with increased levels of CRP in patients with acute ischemic stroke. Therefore, CRP could be a part of the pathophysiological pathway linking OSAS to stroke.
Role of obesity
In patients with OSAS, the increased CRP levels are still under critisism, because of the impact of confounding factors such as obesity, other CVDs and medications. Although, several studies have indicated independent associations between CRP levels and OSAS[19-23,36-38], others do not demonstrate significant correlations after adjustment for associated confounding variables[39-42]. It is possible that OSAS alone may not contribute substantially to CVD since multiple factors have been implicated in the occurrence of CVDs in high-risk patients. Among them, metabolic parameters are important factors, since metabolic syndrome is closely related to cardiovascular morbidity and mortality[43,44].
One should keep in mind that obesity is prevalent in patients with OSAS, and it has been shown that elevated CRP levels are significantly and independently correlated to high BMI. Similarly, other investigators found that CRP levels in OSAS strongly correlate to obesity and not to OSAS severity[42,46,47]. Therefore, based on these studies as nonobese OSAS patients don’t demonstrate statistically increased levels of CRP, any CRP elevation noted in obese OSAS patients may reflect chronic inflammation attributable to obesity and not to chronic hypoxia due to OSAS. Furthermore, it is likely that by interacting with obesity, OSAS further increases systemic inflammation and therefore increases the CRP levels in obese OSAS patients compared to obese without OSAS.
Recent studies, however, have shown a close correlation of CRP level with OSAS severity meaning that the higher the AHI, the higher the levels and CRP elevation seems to be independent from visceral obesity in patients with OSAS[4,19,21,24,34,38,48-54]. The above studies imply that factors other than adiposity may have a central role for the proinflammatory status observed in OSAS.
ROLE OF GENDER
It is worth noting that gender has been considered as a variable in CRP evaluation. A number of studies have also presented higher CRP levels in women compared to men[19-23,36,37,39,51,56-59], probably due to a greater degree of adiposity in women[56,59]. Previously we have shown that moderate to severe OSAS females patients had higher although not statistically significant CRP values, compared to matched males, and more recently Yardim-Akaydin et al showed statistically significant increased values of CRP, in female OSAS patients.
EFFECT OF EXERCISE
There is no agreement in the scientific literature regarding the correlation between exercise and CRP levels. Cavagnolli et al evaluated the effects of aerobic exercise on CRP in non-obese patients with OSAS and found that CRP levels were not elevated and did not change after 2 mo of physical exercise.
As CVDs are detrimental to human health, medical practitioners seek to predict the development of cardiovascular events before they occur. For this reason, the evaluation of CRP as a circulating biomarkers of inflammation has become a useful tool for stratifying patients at high risk for future cardiovascular events. CRP is a relevant marker worthy of further study, because not only is elevated in patients with OSAS, but also is rapidly becoming a risk factor for cardiac disease. Furthermore, in selected OSAS patients, aggressive treatment of the disorder may lead to retarding or even improvement of CVD progression.
CRP has also captured researchers attention, because tests measuring their levels are widely available even in general hospitals. High-sensitivity assays to detect low concentrations of the protein have become available, permitting CRP levels measurement as low as 0.007 mg/L. Contrary to other cytokines, CRP levels are quite stable in the same individual over 24 h and may reflect the level of inflammatory response, without concern for time of day. Furthermore, the American Heart Association approves the use of CRP in risk factor estimation in adults without CVD.
EFFECT OF POSITIVE AIRWAY PRESSURE THERAPY ON LEVELS OF CRP
Positive airway pressure (PAP), mechanically splints the upper airway, thus preventing soft tissue of upper airway from narrowing and collapsing during sleep, has been considered as the most effective treatment for OSAS. Nevertheless, studies concerning the effects of PAP therapy on CRP levels are also contradictory. Among those, most studies had small sample size, which is prone to a false or spurious conclusion.
Our group and others have shown a gradual decrease of CRP levels with effective PAP therapy, which could subsequently improve cardiovascular morbidity associated with OSAS[19,65-69], whereas others found that PAP therapy did not significant change CRP levels, regardless of PAP therapy duration[39,42,65,70-74]. Furthermore our study showed that after PAP therapy CRP was decreased more slowly in females compared to matched for OSAS severity males. CRP levels in females remained unaltered for the first 3 mo, irrespective of effective PAP treatment, while on the contrary males presented a significant fall in CRP over that period. At 6-mo, a significant decrease was observed in all patients who used PAP, while CRP values approached those of subjects without OSAS. A recent meta-analysis on the influence of PAP therapy on CRP levels in OSAS concluded that at least 3 mo of treatment is required to significantly decrease levels indicating that the inflammatory process is still active through this period. CRP levels further declined after 6 mo of PAP treatment. Furthermore, Xie et al also showed a significant decrease on CRP levels, with better benefits with therapy duration of ≥ 3 mo and more adequate compliance (≥ 4 h/night). A previous meta-analysis showed PAP therapy to significantly reduce CRP levels, by 0.11 mg/dL, or 17.8%. In another study we observed that the division of the patients into a good and a poor PAP compliance group affected CRP evolution, with the good PAP compliance group to show exclusively a statistically significant decrease after 6 mo therapy. Although CRP levels were decreased in the poor compliance group, only a statistically significant trend was observed after 1 year of treatment. Based on that, assuming that PAP use is not adequate according to the generally accepted criteria (use < 4 h per night and < 5 d per week), there is not sufficient influence on OSAS-related cardiovascular sequalae. Once again, as CRP is only a component in the complicated inflammatory process which characterizes OSAS, the evolution of other markers should be considered in order to have final conclusions.
Since CVDs are detrimental to human health, medical practitioners seek to predict the development of cardiovascular events before they occur. CRP has been the most studied inflammatory protein to date and a frequently used marker to predict the occurrence of CVDs. Unfortunately, the true correlation between CRP and OSAS is open to controversy, as well as the clinical effect of any reduction. CRP is only one element of the underlying noxius inflammatory process in OSAS. However, there is a shortage of simple, standardized, and cost-effective methods for patient follow-up, and CRP presents these features. In this way, CRP might be valuable along with all other parameters used for the follow-up of patients with OSAS in PAP clinics. Further research is required to define those OSAS patients who will have a considerable reduction with treatment, as well as to understand the significance of the interaction between cardiovascular risk factor and CRP reduction in patients with OSAS.
P- Reviewer: Friedman EA, Leone A, Schoenhagen P S- Editor: Song XX L- Editor: A E- Editor: Lu YJ
Diagnostic and Coding Manual; American Academy of Sleep Medicine. International Classification of Sleep Disorders.2nd ed. Westchester, Ill: American Academy of Sleep Medicine 2005; .
Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.Lancet. 2005;365:1046-1053.
Baguet JP, Hammer L, Lévy P, Pierre H, Launois S, Mallion JM, Pépin JL. The severity of oxygen desaturation is predictive of carotid wall thickening and plaque occurrence.Chest. 2005;128:3407-3412.
Kohli P, Balachandran JS, Malhotra A. Obstructive sleep apnea and the risk for cardiovascular disease.Curr Atheroscler Rep. 2011;13:138-146.
Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?Thorax. 2009;64:631-636.
Meier-Ewert HK, Ridker PM, Rifai N, Price N, Dinges DF, Mullington JM. Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects.Clin Chem. 2001;47:426-430.
Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus.J Am Coll Cardiol. 2007;49:2129-2138.
Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death.Circulation. 2002;105:2595-2599.
Koenig W, Sund M, Fröhlich M, Fischer HG, Löwel H, Döring A, Hutchinson WL, Pepys MB. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992.Circulation. 1999;99:237-242.
Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB, Ridker PM. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study.JAMA. 2002;288:980-987.
Kohler M, Stradling JR. Mechanisms of vascular damage in obstructive sleep apnea.Nat Rev Cardiol. 2010;7:677-685.
Drager LF, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: an emerging risk factor for atherosclerosis.Chest. 2011;140:534-542.
Yamauchi M, Kimura H. Oxidative stress in obstructive sleep apnea: putative pathways to the cardiovascular complications.Antioxid Redox Signal. 2008;10:755-768.
Yamauchi M, Tamaki S, Tomoda K, Yoshikawa M, Fukuoka A, Makinodan K, Koyama N, Suzuki T, Kimura H. Evidence for activation of nuclear factor kappaB in obstructive sleep apnea.Sleep Breath. 2006;10:189-193.
Ryan S, McNicholas WT, Taylor CT. A critical role for p38 map kinase in NF-kappaB signaling during intermittent hypoxia/reoxygenation.Biochem Biophys Res Commun. 2007;355:728-733.
Reynolds GD, Vance RP. C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas.Arch Pathol Lab Med. 1987;111:265-269.
Poston RN, Haskard DO, Coucher JR, Gall NP, Johnson-Tidey RR. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques.Am J Pathol. 1992;140:665-673.
Nelken NA, Coughlin SR, Gordon D, Wilcox JN. Monocyte chemoattractant protein-1 in human atheromatous plaques.J Clin Invest. 1991;88:1121-1127.
Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea.Circulation. 2002;105:2462-2464.
Kokturk O, Ciftci TU, Mollarecep E, Ciftci B. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome.Int Heart J. 2005;46:801-809.
Punjabi NM, Beamer BA. C-reactive protein is associated with sleep disordered breathing independent of adiposity.Sleep. 2007;30:29-34.
Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.Circulation. 2003;107:1129-1134.
Hayashi M, Fujimoto K, Urushibata K, Takamizawa A, Kinoshita O, Kubo K. Hypoxia-sensitive molecules may modulate the development of atherosclerosis in sleep apnoea syndrome.Respirology. 2006;11:24-31.
Nadeem R, Molnar J, Madbouly EM, Nida M, Aggarwal S, Sajid H, Naseem J, Loomba R. Serum inflammatory markers in obstructive sleep apnea: a meta-analysis.J Clin Sleep Med. 2013;9:1003-1012.
Young T, Peppard P. Sleep-disordered breathing and cardiovascular disease: epidemiologic evidence for a relationship.Sleep. 2000;23 Suppl 4:S122-S126.
Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study.Am J Respir Crit Care Med. 2001;163:19-25.
Cano-Pumarega I, Durán-Cantolla J, Aizpuru F, Miranda-Serrano E, Rubio R, Martínez-Null C, de Miguel J, Egea C, Cancelo L, Alvarez A. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort.Am J Respir Crit Care Med. 2011;184:1299-1304.
Fletcher EC, Lesske J, Behm R, Miller CC, Stauss H, Unger T. Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea.J Appl Physiol (1985). 1992;72:1978-1984.
Lesske J, Fletcher EC, Bao G, Unger T. Hypertension caused by chronic intermittent hypoxia--influence of chemoreceptors and sympathetic nervous system.J Hypertens. 1997;15:1593-1603.
Chung MK, Martin DO, Sprecher D, Wazni O, Kanderian A, Carnes CA, Bauer JA, Tchou PJ, Niebauer MJ, Natale A. C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation.Circulation. 2001;104:2886-2891.
Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BH, Witteman JC. C-reactive protein and risk of heart failure. The Rotterdam Study.Am Heart J. 2006;152:514-520.
Michowitz Y, Arbel Y, Wexler D, Sheps D, Rogowski O, Shapira I, Berliner S, Keren G, George J, Roth A. Predictive value of high sensitivity CRP in patients with diastolic heart failure.Int J Cardiol. 2008;125:347-351.
Testelmans D, Tamisier R, Barone-Rochette G, Baguet JP, Roux-Lombard P, Pépin JL, Lévy P. Profile of circulating cytokines: impact of OSA, obesity and acute cardiovascular events.Cytokine. 2013;62:210-216.
Zhao Q, Liu ZH, Zhao ZH, Luo Q, McEvoy RD, Zhang HL, Wang Y. Effects of obstructive sleep apnea and its treatment on cardiovascular risk in CAD patients.Respir Med. 2011;105:1557-1564.
Dziewas R, Ritter M, Kruger L, Berger S, Langer C, Kraus J, Dittrich R, Schabitz WR, Ringelstein EB, Young P. C-reactive protein and fibrinogen in acute stroke patients with and without sleep apnea.Cerebrovasc Dis. 2007;24:412-417.
Can M, Açikgöz S, Mungan G, Bayraktaroğlu T, Koçak E, Güven B, Demirtas S. Serum cardiovascular risk factors in obstructive sleep apnea.Chest. 2006;129:233-237.
Lui MM, Lam JC, Mak HK, Xu A, Ooi C, Lam DC, Mak JC, Khong PL, Ip MS. C-reactive protein is associated with obstructive sleep apnea independent of visceral obesity.Chest. 2009;135:950-956.
Lin QC, Chen LD, Yu YH, Liu KX, Gao SY. Obstructive sleep apnea syndrome is associated with metabolic syndrome and inflammation.Eur Arch Otorhinolaryngol. 2014;271:825-831.
Barceló A, Barbé F, Llompart E, Mayoralas LR, Ladaria A, Bosch M, Agustí AG. Effects of obesity on C-reactive protein level and metabolic disturbances in male patients with obstructive sleep apnea.Am J Med. 2004;117:118-121.
Guilleminault C, Kirisoglu C, Ohayon MM. C-reactive protein and sleep-disordered breathing.Sleep. 2004;27:1507-1511.
Taheri S, Austin D, Lin L, Nieto FJ, Young T, Mignot E. Correlates of serum C-reactive protein (CRP)--no association with sleep duration or sleep disordered breathing.Sleep. 2007;30:991-996.
Ryan S, Nolan GM, Hannigan E, Cunningham S, Taylor C, McNicholas WT. Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity.Thorax. 2007;62:509-514.
Hu G, Qiao Q, Tuomilehto J. The metabolic syndrome and cardiovascular risk.Curr Diabetes Rev. 2005;1:137-143.
Ardern CI, Janssen I. Metabolic syndrome and its association with morbidity and mortality.Appl Physiol Nutr Metab. 2007;32:33-45.
Lee LA, Chen NH, Huang CG, Lin SW, Fang TJ, Li HY. Patients with severe obstructive sleep apnea syndrome and elevated high-sensitivity C-reactive protein need priority treatment.Otolaryngol Head Neck Surg. 2010;143:72-77.
Sharma SK, Mishra HK, Sharma H, Goel A, Sreenivas V, Gulati V, Tahir M. Obesity, and not obstructive sleep apnea, is responsible for increased serum hs-CRP levels in patients with sleep-disordered breathing in Delhi.Sleep Med. 2008;9:149-156.
Su MC, Chen YC, Huang KT, Wang CC, Lin MC, Lin HC. Association of metabolic factors with high-sensitivity C-reactive protein in patients with sleep-disordered breathing.Eur Arch Otorhinolaryngol. 2013;270:749-754.
Guven SF, Turkkani MH, Ciftci B, Ciftci TU, Erdogan Y. The relationship between high-sensitivity C-reactive protein levels and the severity of obstructive sleep apnea.Sleep Breath. 2012;16:217-221.
Zouaoui Boudjeltia K, Van Meerhaeghe A, Doumit S, Guillaume M, Cauchie P, Brohée D, Vanhaeverbeek M, Kerkhofs M. Sleep apnoea-hypopnoea index is an independent predictor of high-sensitivity C-reactive protein elevation.Respiration. 2006;73:243-246.
Peled N, Kassirer M, Shitrit D, Kogan Y, Shlomi D, Berliner AS, Kramer MR. The association of OSA with insulin resistance, inflammation and metabolic syndrome.Respir Med. 2007;101:1696-1701.
Saletu M, Nosiska D, Kapfhammer G, Lalouschek W, Saletu B, Benesch T, Zeitlhofer J. Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis.J Neurol. 2006;253:746-752.
Kapsimalis F, Varouchakis G, Manousaki A, Daskas S, Nikita D, Kryger M, Gourgoulianis K. Association of sleep apnea severity and obesity with insulin resistance, C-reactive protein, and leptin levels in male patients with obstructive sleep apnea.Lung. 2008;186:209-217.
Chung S, Yoon IY, Shin YK, Lee CH, Kim JW, Lee T, Choi DJ, Ahn HJ. Endothelial dysfunction and C-reactive protein in relation with the severity of obstructive sleep apnea syndrome.Sleep. 2007;30:997-1001.
Ye J, Liu H, Li Y, Liu X, Zhu JM. Increased serum levels of C-reactive protein and matrix metalloproteinase-9 in obstructive sleep apnea syndrome.Chin Med J (Engl). 2007;120:1482-1486.
Piéroni L, Bastard JP, Piton A, Khalil L, Hainque B, Jardel C. Interpretation of circulating C-reactive protein levels in adults: body mass index and gender are a must.Diabetes Metab. 2003;29:133-138.
Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, Wians FH, Grundy SM, de Lemos JA. Race and gender differences in C-reactive protein levels.J Am Coll Cardiol. 2005;46:464-469.
Lakoski SG, Cushman M, Criqui M, Rundek T, Blumenthal RS, D’Agostino RB, Herrington DM. Gender and C-reactive protein: data from the Multiethnic Study of Atherosclerosis (MESA) cohort.Am Heart J. 2006;152:593-598.
Ford ES, Giles WH, Mokdad AH, Myers GL. Distribution and correlates of C-reactive protein concentrations among adult US women.Clin Chem. 2004;50:574-581.
Khera A, Vega GL, Das SR, Ayers C, McGuire DK, Grundy SM, de Lemos JA. Sex differences in the relationship between C-reactive protein and body fat.J Clin Endocrinol Metab. 2009;94:3251-3258.
Mermigkis C, Bouloukaki I, Mermigkis D, Kallergis E, Mavroudi E, Varouchakis G, Tzortzaki E, Siafakas N, Schiza SE. CRP evolution pattern in CPAP-treated obstructive sleep apnea patients. Does gender play a role?Sleep Breath. 2012;16:813-819.
Yardim-Akaydin S, Caliskan-Can E, Firat H, Ardic S, Simsek B. Influence of gender on C-reactive protein, fibrinogen, and erythrocyte sedimentation rate in obstructive sleep apnea.Antiinflamm Antiallergy Agents Med Chem. 2014;13:56-63.
Cavagnolli DA, Esteves AM, Ackel-D’Elia C, Maeda MY, de Faria AP, Tufik S, de Mello MT. Aerobic exercise does not change C-reactive protein levels in non-obese patients with obstructive sleep apnoea.Eur J Sport Sci. 2014;14 Suppl 1:S142-S147.
Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay.Clin Chem. 1999;45:2136-2141.
Epstein LJ, Kristo D, Strollo PJ, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults.J Clin Sleep Med. 2009;5:263-276.
Schiza SE, Mermigkis C, Panagiotis P, Bouloukaki I, Kallergis E, Tzanakis N, Tzortzaki E, Vlachaki E, Siafakas NM. C-reactive protein evolution in obstructive sleep apnoea patients under CPAP therapy.Eur J Clin Invest. 2010;40:968-975.
Steiropoulos P, Kotsianidis I, Nena E, Tsara V, Gounari E, Hatzizisi O, Kyriazis G, Christaki P, Froudarakis M, Bouros D. Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome.Sleep. 2009;32:537-543.
Ishida K, Kato M, Kato Y, Yanagihara K, Kinugasa Y, Kotani K, Igawa O, Hisatome I, Shigemasa C, Somers VK. Appropriate use of nasal continuous positive airway pressure decreases elevated C-reactive protein in patients with obstructive sleep apnea.Chest. 2009;136:125-129.
Steiropoulos P, Tsara V, Nena E, Fitili C, Kataropoulou M, Froudarakis M, Christaki P, Bouros D. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome.Chest. 2007;132:843-851.
Panoutsopoulos A, Kallianos A, Kostopoulos K, Seretis C, Koufogiorga E, Protogerou A, Trakada G, Kostopoulos C, Zakopoulos N, Nikolopoulos I. Effect of CPAP treatment on endothelial function and plasma CRP levels in patients with sleep apnea.Med Sci Monit. 2012;18:CR747-CR751.
Akashiba T, Akahoshi T, Kawahara S, Majima T, Horie T. Effects of long-term nasal continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea syndrome.Intern Med. 2005;44:899-900.
Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome.Chest. 2008;134:686-692.
Burioka N, Koyanagi S, Endo M, Takata M, Fukuoka Y, Miyata M, Takeda K, Chikumi H, Ohdo S, Shimizu E. Clock gene dysfunction in patients with obstructive sleep apnoea syndrome.Eur Respir J. 2008;32:105-112.
Chung S, Yoon IY, Lee CH, Kim JW. The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.Sleep Breath. 2011;15:71-76.
Al-Shaer MH, Shammas NW, Lemke JH, Kapalis MJ, Dippel EJ, Harb H, Reddy G, McKinney D, Mahadevia AK. CPAP does not reduce high-sensitivity C-reactive protein in patients with coronary artery disease and obstructive sleep apnea.Int J Angiol. 2005;14:129-132.
Guo Y, Pan L, Ren D, Xie X. Impact of continuous positive airway pressure on C-reactive protein in patients with obstructive sleep apnea: a meta-analysis.Sleep Breath. 2013;17:495-503.
Xie X, Pan L, Ren D, Du C, Guo Y. Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: a meta-analysis.Sleep Med. 2013;14:1139-1150.
Friedman M, Samuelson CG, Hamilton C, Fisher M, Kelley K, Joseph NJ, Wang PC, Lin HC. Effect of continuous positive airway pressure on C-reactive protein levels in sleep apnea: a meta-analysis.Otolaryngol Head Neck Surg. 2012;147:423-433.
Chami HA, Fontes JD, Vasan RS, Keaney JF, O’Connor GT, Larson MG, Benjamin EJ, Gottlieb DJ. Vascular inflammation and sleep disordered breathing in a community-based cohort.Sleep. 2013;36:763-768C.
Kurt OK, Yildiz N. The importance of laboratory parameters in patients with obstructive sleep apnea syndrome.Blood Coagul Fibrinolysis. 2013;24:371-374.
Svensson M, Venge P, Janson C, Lindberg E. Relationship between sleep-disordered breathing and markers of systemic inflammation in women from the general population.J Sleep Res. 2012;21:147-154.