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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 25  |  Issue : 2  |  Page : 86-91

Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea


1 Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Respiratory Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
3 Department of Clinical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission21-Jan-2013
Date of Acceptance27-Jan-2013
Date of Web Publication4-Jul-2014

Correspondence Address:
Abir Zakaria
Department of Internal Medicine, 158 Haram Street, MIRAC Center, Building 2A, First Floor, Number 10, 12555 Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJIM.0000428097.62173.17

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  Abstract 

Background

Obstructive sleep apnea (OSA) syndrome is associated with cardiovascular complications attributed to endothelial dysfunction. There are contradictory reports on whether lactoferrin is protective or injurious to the blood vessels.

Objectives

To determine circulating plasma lactoferrin level in OSA patients in relation to endothelial dysfunction and to assess its relation to other criteria of OSA.

Patients and methods

In a cross-sectional study, 40 OSA patients were recruited after an established diagnosis in the sleep laboratory of the pulmonary medicine department. Doppler flow-mediated dilatation percentage (FMD%) was tested as an indicator of endothelial function. Anthropometric measurements, systolic and diastolic blood pressure, lipid profile, plasma lactoferrin level, fasting, and 2 h postprandial plasma glucose (PPG) were estimated in the patients and the control groups. Moreover, the apnea–hypopnea index, and the mean and nadir nocturnal oxygen saturation of OSA patients were determined.

Results

OSA patients were found to have significantly higher BMI, waist circumference (WC), neck circumference, fasting plasma glucose (FPG), 2 h PPG, low-density lipoprotein-cholesterol, and lower plasma lactoferrin, FMD%, and high-density lipoprotein (HDL)-cholesterol compared with the control group. There was a significant direct correlation between FMD%, as an indicator of endothelial function, and plasma lactoferrin level as well as HDL-cholesterol, and an inverse correlation between FMD% and BMI, WC, FPG, 2 h PPG, and basal brachial artery diameter. Multiple regression analysis showed that lactoferrin was the only independent predictor for FMD% among OSA patients.

However, plasma lactoferrin level was inversely correlated with BMI, WC, FPG, and 2 h PPG, and was directly correlated with HDL-cholesterol and FMD%. Multiple regression analysis selected BMI and FMD% as the independent predictors for lactoferrin level.

Conclusion

The present study showed that low circulating plasma lactoferrin levels in OSA patients independently predict endothelial dysfunction as assessed by FMD%. High BMI in OSA patients negatively influences plasma lactoferrin levels unrelated to other OSA severity predictors.

Keywords: endothelial dysfunction, flow-mediated dilatation, lactoferrin, obstructive sleep apnea


How to cite this article:
Zakaria A, El Shazly M, Rashed L. Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea. Egypt J Intern Med 2013;25:86-91

How to cite this URL:
Zakaria A, El Shazly M, Rashed L. Plasma lactoferrin level as a predictor to endothelial dysfunction in patients with obstructive sleep apnea. Egypt J Intern Med [serial online] 2013 [cited 2019 Jul 23];25:86-91. Available from: http://www.esim.eg.net/text.asp?2013/25/2/86/135866


  Introduction Top


Lactoferrin is an iron-binding glycoprotein of the transferrin family. It was found to be released from degranulation of neutrophils upon stimulation 1 and to inhibit upregulation of adhesion molecules on endothelial cells in addition to its known antimicrobial function. Moreover, it was known to inhibit tumor-induced blood vessels 2. However, in a recent population-based prospective study, elevated basal lactoferrin was found to be a predictor of future fatal ischemic heart disease 1. Therefore, there is an apparent contradiction on the effect of lactoferrin on endothelial function, whether protective or harmful.

Obstructive sleep apnea (OSA) is considered a risk factor for cardiovascular diseases, including hypertension, coronary heart disease, and strokes 3. Endothelial dysfunction, found in previous studies to be associated with OSA 4, can be considered as a preclinical predictor of future vascular events 5. Endothelial dysfunction among OSA patients has many proposed as a pathogenic mechanism including oxidative stress 6, endothelial apoptosis 3, and inflammatory injury 7. Whether lactoferrin defends or injures the endothelium in the pathogenesis of OSA remains to be elucidated.


  Objectives of the study Top


In the current study, we aimed to detect the level of circulating plasma lactoferrin in relation to endothelial dysfunction, as assessed by flow-mediated dilatation percentage (FMD%), in OSA patients. We attempted to sort the importance of lactoferrin level among other indicators of OSA severity, such as the apnea–hypopnea index (AHI), mean and nadir nocturnal oxygen saturation, as modulators of endothelial function. Central obesity, hypertension, glucose intolerance, or diabetes mellitus, found to be more prevalent among patients with OSA, compared with healthy individuals, were also taken into consideration as factors that might influence endothelial function.


  Participants and methods Top


In a cross-sectional study, carried out in Kasr El Ainy Hospital from May 2010 to December 2010, FMD% of the right brachial artery, as an indicator of the endothelial-derived vasodilatation, was compared between 40 consecutive patients (27 men and 13 women, age range 40–60 years) with an established diagnosis of OSA and apparently healthy age-matched 40 individuals (28 men and 12 women) as a control group. Circulating plasma lactoferrin level was compared between OSA patients and controls. The study design was approved by the medical ethical committee of the Internal Medicine Department, Faculty of Medicine, Cairo University, Egypt. An informed written consent was obtained from each participating patient as well.

In OSA patients, as well as the control group, we estimated anthropometric measurements comprising BMI, calculated as the weight in kg divided by the height in m2, waist circumference (WC), measured by a soft tape midway between the lowest rib and the iliac crest, and neck circumference (NC), measured at the base of the neck. Systolic and diastolic blood pressure were measured in the right arm after 10 min of rest, using a standard sphygmomanometer with an appropriate cuff size, with the first and the fifth sounds considered to represent systolic and diastolic blood pressure readings, respectively. The mean of three blood pressure readings taken 5 min apart was calculated. Fasting and 2 h postprandial plasma glucose (PPG), total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein-cholesterol, and triglycerides were also estimated. Indicators of OSA severity such as AHI, mean and nadir nocturnal oxygen saturation were assessed in the patient group.

Patients with heart failure, chronic pulmonary disease, chronic renal or liver disease, smokers, or those with acute upper respiratory tract infection were excluded from the present study.

Polysomnography

In the sleep laboratory of the respiratory medicine department, overnight polysomnography was carried out. According to the AHI, defined as the total number of complete or partial cessation of breathing per one sleeping hour, caused by airway obstruction, OSA was classified into mild (AHI 5–15), moderate (AHI 15–30), and severe (AHI>30). Moreover, nadir and mean nocturnal oxygen saturation were recorded and calculated, respectively.

Vascular reactivity assessment

Vascular endothelial-dependent reactivity assessment was performed in the vascular laboratory of the medical emergency department. Using the B-mode image of duplex ultrasound, the basal diameter of the right brachial artery was measured in the patients with OSA and in the control group after being rested in the supine position in a quiet room for 10 min. Reactive hyperemia was induced by inflating a pneumatic tourniquet distal to the brachial artery to 50 mmHg above the systolic blood pressure for 5 min. After cuff deflation and within 1 min, the diameter of the brachial artery was measured again. Arterial diameter was measured as the distance between the lumen–intima interface of the near and the far walls, as averaged from three consecutive end-diastolic measurements, guided by the R-wave of the associated electrocardiogram, whether in the basal or in the posthyperemic phase. FMD% was defined as the percent change in brachial artery diameter between the basal and the posthyperemic phase. An ATL HDI 5000 (Washington, USA) ultrasound machine was used for the duplex ultrasound study of the brachial artery using a 7.5-MHz linear transducer.

Estimation of plasma lactoferrin level

Plasma lactoferrin levels were measured using the BIOXYTECH lactof EIA reagent set (Oxis Research, Portland, USA). Plasma samples were diluted and assayed according to the manufacturer’s instructions. Intra-assay and interassay imprecision was between 5 and 10%. The lower detection limit of the assay is 1 µg/l and the degree of cross-reactivity with transferrin was less than 1%.

Statistical methods

Data were statistically described in terms of mean±SD, median and range, or frequencies (number of cases) and percentages when appropriate. Comparison of numerical variables between the study groups was carried out using the Student t-test for independent samples when comparing two groups and the one-way analysis of variance test with post-hoc multiple two-group comparisons when comparing more than two groups. For comparison of sex, the χ2-test was carried out. Correlation between various variables was determined using the Pearson moment correlation equation. Multivariate analysis models were used to test for the preferential effect of all studied variable(s) on FMD% values among OSA cases. A P-value less than 0.05 was considered statistically significant. All statistical calculations were carried out using computer programs statistical package for the social science (SPSS; SPSS Inc., Chicago, Illinois, USA) version 15 for Microsoft Windows.


  Results Top


OSA patients showed significantly higher BMI, WC, NC, fasting plasma glucose (FPG), 2 h PPG, low-density lipoprotein-cholesterol, and lower plasma lactoferrin, FMD%, and HDL-cholesterol compared with the control group [Table 1].
Table 1: Comparison between obstructive sleep apnea patients and the control group

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By subclassification of OSA patients according to AHI into mild, moderate, and severe types, only NC showed a statistically significant difference between subgroups (P=0.000).

A statistically significant positive correlation was detected between FMD% and plasma lactoferrin level as well as HDL-cholesterol, whereas a significant negative correlation existed between FMD% on the one hand and BMI, WC, FPG, 2 h PPG, and basal brachial artery diameter on the other [Table 2].
Table 2: Correlation between flow-mediated dilatation percentage and other variables in obstructive sleep apnea patients

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Multiple regression analysis, including all the significantly correlated variables, showed that plasma lactoferrin level was the only independent predictor for FMD%, among OSA patients. The positive correlation between plasma lactoferrin level and FMD% is shown in [Figure 1].
Figure 1: Correlation between FMD% and plasma lactoferrin among obstructive sleep apnea cases. FMD%, flow-mediated dilatation percentage; LF, plasma lactoferrin.

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Lactoferrin level was correlated inversely with BMI, WC, FPG, and 2 h PPG, and was correlated directly with HDL-cholesterol and FMD% [Table 3]. Multiple regression analysis selected BMI and FMD% as the independent predictors for lactoferrin level.
Table 3: Correlation between lactoferrin and other variables in obstructive sleep apnea patients

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  Discussion Top


OSA is a disorder characterized by recurrent attacks of breathing cessation during sleep because of upper airway obstruction, with frequent arousal attempts because of maintained efforts of breathing. The latter causes sleep deprivation and daytime tiredness in patients 8. OSA was found to be associated with adverse cardiovascular events including hypertension, coronary heart disease, and cerebrovascular strokes, found more frequently in OSA patients in comparison with non-OSA patients 5,9. The pathophysiologic mechanism contributing to cardiovascular adverse events in OSA patients needs more elucidation. Endothelial dysfunction was suggested in previous studies to explain this phenomenon 10. Many potential etiologies have been proposed for such a dysfunction, including repeated attacks of hypoxemia, followed by reoxygenation, with subsequent generation of reactive oxygen species 6, which exert an inflammatory effect on the endothelium. Increase in activated circulating leukocytes was also a proposed mechanism of oxidant overproduction with subsequent endothelial dysfunction in OSA patients 11,12. Lactoferrin is an 80-kDa monomeric multifunctional nonheme iron-binding glycoprotein, comprising two lobes, each of which binds a ferric iron. It has been suggested to show anti-inflammatory, immunomodulatory, and antitumoral effects 13. Previous studies have shown the existence of lactoferrin receptors in the monocytes, lymphocytes, adipocytes, hepatocytes, and endothelial cells 14.

In the current study, OSA patients showed significantly higher BMI. This is in agreement with previous studies 15–18. The Wisconsin Sleep Cohort study concluded that each one standard deviation of BMI was associated with a four-fold increase in the prevalence of OSA 15. Other studies proved that elevation of BMI above a cutoff level, suggested in one study to be 40 kg/m2 16, and in another one to be 30 kg/m2 17, increased susceptibility to OSA. Combined with a simple snoring severity score, BMI was suggested by other investigators 18 as a useful method for screening of patients, who will be referred to polysomnography.

Central rather than peripheral distribution of obesity evidenced by WC and NC were found in the Sleep Heart Health study to be independently associated with moderate-to-severe OSA, defined as AHI of 15 times/h or more 19. This was in agreement with the present study, which showed a significant increase in NC associated with OSA deterioration from mild to severe, as assessed by AHI. This was also in agreement with previous investigators, who concluded that NC was a more useful predictor for OSA than general obesity as assessed by BMI in a prospective study and suggested using it for a confident clinical diagnosis of OSA before ordering polysomnography 20.

FMD% was found in the current study to be markedly impaired in OSA patients compared with the control group. This coincided with previous studies showing diminished FMD% in OSA patients 21,22 irrespective of obesity 21, with improvement after uvulopalatopharyngoplasty 22.

Moreover, FMD% in the present study showed a significant inverse correlation with BMI, WC, FPG, and 2 h PPG, and a significant positive correlation with plasma lactoferrin level and HDL-cholesterol. This was in agreement with previous studies that suggested a relation between impaired FMD% and obesity, especially central type, and insulin resistance 23. Increased number and size of adipocytes was considered to induce functional abnormalities in the endoplasmic reticulum and mitochondria, with subsequent enhancement of the proinflammatory state disrupting the balance between proinflammatory and anti-inflammatory pathways, aggravating insulin resistance and enhancing excessive production of free fatty acids 24. Central obesity is recognized as a chronic subclinical inflammatory state in which many inflammatory mediators such as interleukin-6, tumor necrosis factor-α, serum retinol binding protein-4, and plasminogen activator inhibitor-1 are operating 24. Interleukin-6 is claimed to induce C-reactive protein production by the liver 25. C-reactive protein inhibits nitric oxide formation by the endothelial cells promoting vasoconstriction and hence endothelial dysfunction 24. Moreover, in obese patients, several free fatty acids, exceeding the capacity of adipose tissue, are found to accumulate in nonadipose tissues such as the liver, inducing overproduction of metabolic toxins 25, with additional impairment of insulin signaling and glucose tolerance 26.

The current study showed a significant positive correlation between circulating plasma lactoferrin level and FMD%, with the former determined to be the only independent predictor for FMD% after multiple regression analysis. This finding emphasized the protective effect of lactoferrin on the endothelium in agreement with other studies, which explained this anti-inflammatory role of lactoferrin by its iron-sequestering ability, preventing the formation of reactive oxygen species by the human body and depriving the invading organism from iron, being an important nutrient for microorganisms. However, this analysis was in context of the antimicrobial role of lactoferrin 27. Moreover, lactoferrin was proved by other investigators to prevent the release of cytokines responsible for activation and recruitment of leukocytes in inflamed tissues, with the latter suggested to exert a deleterious effect on the endothelium 28–30.

Our findings seemed apparently contradictory to the conclusions drawn by Vengen et al. 1, who showed that elevation of serum lactoferrin level strongly predicted the long-term risk for fatal coronary artery disease and hence endothelial dysfunction among the diabetic subgroup of their participating cohort. However, these researchers suggested that the anti-inflammatory effect of lactoferrin may be disturbed in patients with diabetes, increasing their atherosclerotic risk 1. Moreover, others claimed this elevation in serum lactoferrin level to be spurious because of neutrophil degranulation by clot retraction 13. The latter was avoided in the current study by estimation of circulating plasma lactoferrin level.

Plasma lactoferrin level was shown in the present study to be inversely associated with BMI, WC, FPG, and 2 h PPG, and directly correlated with FMD% and HDL-cholesterol, with BMI being recognized as its independent predictor by multiple regression analysis.

This was in agreement with other investigators who proved that lactoferrin correlated positively with endothelial-derived vasodilatation in the obese subgroup of the participants with impaired glucose tolerance 13. The protective effect of lactoferrin on the endothelium was explained by its inhibitory action on upregulation of adhesion molecules on endothelial cells 1. Lactoferrin was also found to induce endothelial-dependent vasodilatation in a nitric oxide-dependent manner 31. Moreover, previous studies showed that lactoferrin affected the peripheral opioid-mediated antinociception in animal models 32,33 through nitric oxide.

Another favorable effect of lactoferrin on lipid profile by increasing HDL-cholesterol has been recognized before in animal models 34. This agreed with the positive correlation between plasma lactoferrin level and HDL-cholesterol in the current study. This was explained by its inhibitory effect on selective HDL-cholesterol esters’ uptake by about 50% in primary human adipocytes and liposarcoma cells 35.

Lactoferrin was recognized by previous researchers to differ from other substances released from activated neutrophils by its unique anti-inflammatory properties, as it suppresses the production of inflammatory cytokines by monocytes, which may be suggested as a feedback mechanism avoiding further neutrophil recruitment and activation 36. Lactoferrin also binds iron, which is considered to catalyze the formation of reactive oxygen species 1, known to increase in OSA patients with a deleterious effect on the endothelium. Thus, the reduced circulating lactoferrin level in OSA patients in the current study might be explained by its consumption, due to excessive reactive oxygen species production following repeated obstructive apnea or hypopnea attacks.

Moreover, lactoferrin was found in the present research to be inversely correlated with fasting and 2 h PPG levels. OSA patients were shown in previous population-based studies to be more susceptible to glucose intolerance and diabetes mellitus 37, with hyperglycemia and advanced glycation end products being suggested to inhibit lactoferrin function 38.

Unexpectedly, the present study identified no significant effect of increased AHI or lowered mean or nadir nocturnal oxygen saturation on endothelial dysfunction among OSA patients, which might be explained by the short duration of study of these variables by polysomnography over one night only. Assessment of average oxygen saturation readings of several days might have shown a significant deleterious effect of low oxygen saturation on FMD% and plasma lactoferrin levels among OSA patients, with hypoxemia always considered to be the cornerstone pathogenic factor of oxidative stress applied on the endothelium.


  Conclusion Top


The current study showed that OSA patients were characterized by lower circulating plasma lactoferrin level, which was proved to be the only independent predictor for endothelial dysfunction evaluated by FMD%. In addition, increased BMI was found to be the independent predictor for lower plasma lactoferrin level in those patients.

Taking the small sample of the current study into consideration warranted its replication in a larger scale among OSA patients, with further verification of the mechanisms of the suggested protective effect of lactoferrin. Its potential clinical usefulness as a marker for response to treatment of OSA by nonsurgical or surgical therapeutic methods, including weight reduction and noninvasive positive pressure ventilation, might also be valuable for study in the future. Prospective studies to examine the effect of animal milk protein ingestion, which contains abundant amounts of lactoferrin 39, as an adjuvant therapy for OSA patients with evaluation of endothelial function might be considered as well.[39]

 
  References Top

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38.Li YM. Glycation ligand binding motif in lactoferrin: implications in diabetic infection. Adv Exp Med Biol. 1998;443:57–63  Back to cited text no. 38
    
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