Usefulness of Fetuin-A to Predict Risk for Cardiovascular Disease Among Patients With Obstructive Sleep Apnea
2015; Elsevier BV; Volume: 116; Issue: 2 Linguagem: Inglês
10.1016/j.amjcard.2015.04.014
ISSN1879-1913
AutoresAlice Liu, Cindy Lamendola, Danit Ariel, Fahim Abbasi, Sun H. Kim, James Cardell, Vanessa Tomasso, Shiming Xu, Shailja Patel, Hafasa Mojaddidi, Kaylene Grove, Clete A. Kushida, Gerald M. Reaven,
Tópico(s)Bariatric Surgery and Outcomes
ResumoPatients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases (CVDs). Fetuin-A, a novel hepatokine, has been associated with the metabolic syndrome (MetS), insulin resistance, and type 2 diabetes mellitus, all of which are highly prevalent in patients with OSA and associated with increased CVD risk. The goal of this study was to determine whether fetuin-A could be involved in the pathogenesis of CVD risk in patients with OSA, through relations of fetuin-A with MetS components and/or insulin resistance. Overweight or obese, nondiabetic volunteers (n = 120) were diagnosed with OSA by in-laboratory nocturnal polysomnography. Steady-state plasma glucose concentrations derived during the insulin suppression test were used to quantify insulin-mediated glucose uptake; higher steady-state plasma glucose concentrations indicated greater insulin resistance. Fasting plasma fetuin-A and lipoprotein concentrations were measured. Whereas neither the prevalence of MetS nor the number of MetS components was associated with tertiles of fetuin-A concentrations, the lipoprotein components of MetS, triglycerides and high-density lipoprotein cholesterol, increased (p <0.01) and decreased (p <0.05), respectively, across fetuin-A tertiles. Additionally, comprehensive lipoprotein analysis revealed that very low density lipoprotein (VLDL) particles and VLDL subfractions (VLDL1+2 and VLDL3) were increased across fetuin-A tertiles. In contrast, neither insulin resistance nor sleep measurements related to OSA were found to be modified by fetuin-A concentrations. In conclusion, abnormalities of lipoprotein metabolism, but not MetS or insulin resistance per se, may represent a mechanism by which fetuin-A contributes to increased CVD risk in patients with OSA. Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases (CVDs). Fetuin-A, a novel hepatokine, has been associated with the metabolic syndrome (MetS), insulin resistance, and type 2 diabetes mellitus, all of which are highly prevalent in patients with OSA and associated with increased CVD risk. The goal of this study was to determine whether fetuin-A could be involved in the pathogenesis of CVD risk in patients with OSA, through relations of fetuin-A with MetS components and/or insulin resistance. Overweight or obese, nondiabetic volunteers (n = 120) were diagnosed with OSA by in-laboratory nocturnal polysomnography. Steady-state plasma glucose concentrations derived during the insulin suppression test were used to quantify insulin-mediated glucose uptake; higher steady-state plasma glucose concentrations indicated greater insulin resistance. Fasting plasma fetuin-A and lipoprotein concentrations were measured. Whereas neither the prevalence of MetS nor the number of MetS components was associated with tertiles of fetuin-A concentrations, the lipoprotein components of MetS, triglycerides and high-density lipoprotein cholesterol, increased (p <0.01) and decreased (p 30 events/hour. Additional measurements included minimum and mean oxygen saturation, and oxygen desaturation index (number of events per hour in which a ≥3% decrease in oxygen saturation occurs from baseline).After a 12-hour fast, patients were admitted to the Stanford Clinical and Translational Research Center. Patients underwent the modified insulin suppression test15Knowles J.W. Assimes T.L. Tsao P.S. Natali A. Mari A. Quertermous T. Reaven G.M. Abbasi F. Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp.Metabolism. 2013; 62: 548-553Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar to quantify insulin-mediated glucose disposal. Participants received intravenous octreotide (0.27 μg/m2/min), insulin (32 mU/m2/min), and glucose (267 mg/m2/min) over 3 hours. During the final 30 minutes, blood was drawn every 10 minutes for measurements of plasma insulin and glucose. These 4 values were averaged to obtain steady-state plasma insulin and steady-state plasma glucose (SSPG) concentrations for each patient. Because steady-state plasma insulin is similar for all subjects, SSPG provides a direct measure of the ability of insulin to mediate disposal of the infused glucose load. Thus, higher SSPG concentrations indicate greater insulin resistance. SSPG is highly correlated with measures derived from the hyperinsulinemic euglycemic clamp (r ≥ −0.87).15Knowles J.W. Assimes T.L. Tsao P.S. Natali A. Mari A. Quertermous T. Reaven G.M. Abbasi F. Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp.Metabolism. 2013; 62: 548-553Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 16Greenfield M.S. Doberne L. Kraemer F. Tobey T. Reaven G. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp.Diabetes. 1981; 30: 387-392Crossref PubMed Google ScholarFasting plasma samples were frozen at −80°C until measurements were performed. Plasma fetuin-A levels were quantified by a human fetuin-A sandwich enzyme-linked immunosorbent assay kit (Epitope Diagnostics, San Diego, California) using 2 polyclonal antibodies that bind to different epitopes of human fetuin-A. Intra-assay precision is 4.8% to 5.5% and interassay precision is 5.7% to 6.8%. Lipoprotein analysis was performed using the VAP Test (Atherotech, Inc., Albuquerque, New Mexico), as described previously.17Liu A. Cardell J. Ariel D. Lamendola C. Abbasi F. Kim S.H. Holmes T.H. Tomasso V. Mojaddidi H. Grove K. Kushida C.A. Reaven G.M. Abnormalities of lipoprotein concentrations in obstructive sleep apnea are related to insulin resistance.Sleep. 2015; 38: 793-799PubMed Google ScholarMetS was defined using the "harmonious" criteria,18Alberti K.G. Eckel R.H. Grundy S.M. Zimmet P.Z. Cleeman J.I. Donato K.A. Fruchart J.C. James W.P. Loria C.M. Smith Jr., S.C. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (9682) Google Scholar of which 3 of the 5 following components must be met: fasting plasma glucose ≥100 mg/dl (5.56 mmol/L), systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥ 85 mm Hg, triglycerides ≥150 mg/dl (1.70 mmol/L), and high-density lipoprotein (HDL) cholesterol <40 mg/dl (1.30 mmol/L) in men and <50 mg/dl (1.04 mmol/L) in women. Criteria for abdominal obesity (for subjects in the United States) included waist circumference ≥88 cm in women and ≥102 cm in men.18Alberti K.G. Eckel R.H. Grundy S.M. Zimmet P.Z. Cleeman J.I. Donato K.A. Fruchart J.C. James W.P. Loria C.M. Smith Jr., S.C. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.Circulation. 2009; 120: 1640-1645Crossref PubMed Scopus (9682) Google ScholarStatistical analyses were performed using IBM SPSS Statistics version 22.0 (IBM, Armonk, New York).Fetuin-A and lipoprotein concentrations that were not normally distributed were log transformed before analysis. Patients were categorized into tertiles of fetuin-A. A generalized linear model (analysis of covariance) to adjust for age, gender, race, and body mass index was used to assess for significant associations between groups. Sequential Bonferroni adjustment was used to adjust p values adjusted for multiple pairwise comparisons. Linear trends of lipoprotein concentrations across tertiles of fetuin-A were estimated using analysis of variance. Chi-square tests were performed to compare MetS prevalence, number of MetS components, and low-density lipoprotein density patterns across tertiles of fetuin. A p value <0.05 indicated statistical significance, and all hypothesis testing was 2 tailed.ResultsBaseline characteristics of the study population are listed in Table 1. Almost 2/3 of the cohort was male. They were middle aged, obese, and had impaired fasting glucose. A substantial proportion met criteria for MetS (43%). They ranged sixfold in degree of insulin sensitivity (SSPG 51 to 309 mg/dl). On average, they had severe OSA (AHI 34.0 events/hour) but were distributed across all categories of OSA severity. Fetuin-A levels did not differ between patients with and those without MetS (0.425 ± 0.10 vs 0.419 ± 0.10 g/L, p = 0.69).Table 1Characteristics of the study population (n = 120)VariableMeanRangeAge (years)50 ± 1030 – 68Men77 (64%)White/ Asian/ Hispanic or Latino/ Black75/ 25/ 15/ 5Body Mass Index (kg/m2)30.6 ± 3.025.7 – 37.9Waist circumference (cm)103 ± 1087 – 131Metabolic syndrome52 (43%)Fasting plasma glucose (mg/dL)102 ± 982 – 123Steady-state plasma glucose (mg/dL)170 ± 6551 – 309Systolic blood pressure (mmHg)125 ± 1399 – 166Diastolic blood pressure (mmHg)79 ± 860 – 98Apnea-hypopnea index (events/hour)34.0 ± 245.2 – 111.8Mild/ moderate/ severe OSA31 (26%)/ 35 (29%) / 54 (45%)Fetuin-A (gram/L)0.42 ± 0.100.26 – 0.91Data are expressed as mean ± S.D. unless otherwise indicated. Open table in a new tab Table 2 evaluates the trend of anthropometric and MetS components across tertiles of fetuin-A. Neither the proportion of patients with MetS (p = 0.53) nor the mean number of MetS components (p = 0.58) was significantly different across groups. Of the individual MetS components, triglycerides increased and HDL cholesterol decreased linearly across fetuin-A tertiles (p <0.05); no differences were detected in the other MetS components.Table 2Comparison of anthropometric and metabolic syndrome components across fetuin-A tertiles in patients with obstructive sleep apneaVariableFetuin TertileP valueP value for trend1( 0.446 g/L)(n=40)Age (years)52 ± 1048 ± 1150 ± 90.310.33Men22 (55%)27 (68%)28 (70%)0.33N/AWhite/Asian//Hispanic/Black26/ 3/ 7/ 422/ 14/ 3/ 127/ 8/ 5/ 00.023N/ABody Mass Index (kg/m2)30.8 ± 330.1 ± 2.831.0 ± 30.430.74Metabolic syndrome15 (38%)20 (50%)17 (43%)0.53N/AMetabolic syndromecomponents2.25 ± 1.12.50 ± 1.22.40 ± 1.30.58N/AWaist circumference (cm)103 ± 10102 ± 9104 ± 110.720.72Fasting plasma glucose (mg/dL)101 ± 9102 ± 10101 ± 90.750.80HDL-C (mg/dL)54 ± 1747 ± 1646 ± 120.0460.02Triglycerides (mg/dL)114 ± 60147 ± 58198 ± 3280.0040.002Systolic blood pressure (mmHg)126 ± 15124 ± 10124 ± 140.840.61Diastolic blood pressure (mmHg)80 ± 879 ± 680 ± 90.991.0Data are expressed as mean ± SD unless otherwise specified. Open table in a new tab To explore the relation between lipoprotein particles and fetuin-A further, comprehensive lipoprotein analysis was performed (Table 3). Triglycerides, very low density lipoprotein (VLDL), and VLDL subfractions (VLDL1+2 and VLDL3) increased across fetuin-A tertiles, indicating a worse lipoprotein profile with higher fetuin-A concentrations. Pairwise comparisons demonstrated that the significant associations for triglycerides, VLDL, VLDL1+2, and VLDL3 were between the upper and lowest tertile of fetuin-A. There was also a linear trend for decreased HDL cholesterol and its subfraction HDL2 across fetuin-A tertiles. Finally, low-density lipoprotein density patterns A, A/B, and B were compared across fetuin-A tertiles, and no differences were detected (p = 0.30).Table 3Comparison of lipoprotein measurements across tertiles of fetuin-A concentrationsVariableFetuin TertileP value∗P-value reflects differences among tertiles after adjustment for age, sex, race, and BMI.P value for trend†P-value for test of linear trend across tertiles.1( 0.446 g/L)(n=40)Total cholesterol (mg/dL)193 ± 47195 ± 42186 ± 360.610.42Total LDL (mg/dL)117 ± 39121 ± 35112 ± 310.570.55 LDL1 (mg/dL)16.3 ± 717.8 ± 816 ± 70.370.94 LDL2 (mg/dL)27 ± 1820 ± 1620 ± 130.250.20 LDL3 (mg/dL)42 ± 2044 ± 1739 ± 160.410.55 LDL4 (mg/dL)11.3 ± 916.8 ± 1314.7 ± 140.090.21IDL (mg/dL)13.4 ± 616.3 ± 615.3 ± 70.070.18Total VLDL (mg/dL)23 ± 1127 ± 928 ± 10‡P< 0.01 for tertile 3 vs tertile 1.0.010.003 VLDL1+2 (mg/dL)9.8 ± 612.2 ± 512.8 ± 6‡P< 0.01 for tertile 3 vs tertile 1.0.010.002 VLDL3 (mg/dL)12.8 ± 514.8 ± 414.7 ± 4§P <0.05 for tertile 3 vs tertile 1.0.020.015Triglycerides (mg/dL)114 ± 60147 ± 58198 ± 328‡P< 0.01 for tertile 3 vs tertile 1.0.0080.002Total HDL (mg/dL)54 ± 1747 ± 1646 ± 120.160.024 HDL2 (mg/dL)14 ± 811 ± 711 ± 50.150.026 HDL3 (mg/dL)39 ± 1136 ± 935 ± 80.970.42Lp(a) (mg/dL)7.3 ± 46.1 ± 56.5 ± 40.390.59Apolipoprotein B (mg/dL)93 ± 24100 ± 2295 ± 220.460.66Apolipoprotein A1 (mg/dL)153 ± 26144 ± 25143 ± 200.420.09Apolipoprotein B/Apolipoprotein A1 ratio0.62 ± 0.20.71 ± 0.20.68 ± 0.20.220.18Data are expressed as mean ± SD unless otherwise specified.∗ P-value reflects differences among tertiles after adjustment for age, sex, race, and BMI.† P-value for test of linear trend across tertiles.‡ P< 0.01 for tertile 3 vs tertile 1.§ P <0.05 for tertile 3 vs tertile 1. Open table in a new tab The relation of fetuin-A with insulin mediated-glucose disposal (SSPG) is displayed in Figure 1. SSPG concentrations did not differ by tertiles of fetuin-A levels (p = 0.50). Furthermore, a significant correlation between fetuin-A and SSPG was not observed (r = 0.03, p = 0.79).Finally, associations between fetuin-A concentrations and sleep parameters were examined. Severity of OSA (AHI) was not different across fetuin-A tertiles (p = 0.79). There were no statistically significant correlations between fetuin-A and AHI (r = −0.08, p = 0.37), minimum oxygen saturation (r = 0.01, p = 0.88), mean oxygen saturation (r = 0.03, p = 0.73), or oxygen desaturation index (r = −0.11, p = 0.22).DiscussionThe purpose of this study was to determine whether fetuin-A could be implicated in mechanisms for CVD risk in patients with OSA, through relations with MetS and/or insulin resistance. Although fetuin-A was not associated with MetS in OSA patients per se, the individual lipoprotein components of MetS, triglycerides and HDL cholesterol, increased and decreased, respectively, across increasing fetuin-A tertiles. Expanded evaluation of lipoproteins extended these findings to include associations with VLDL particles and its subclasses, suggesting that dyslipidemia may be a mechanism by which fetuin-A contributes to increased CVD risk in patients with OSA. In contrast, neither insulin resistance nor OSA severity was found to be modified by fetuin-A.Previous publications have reported associations of fetuin-A with increased prevalence of MetS in general populations that included patients with T2DM19Kaess B.M. Enserro D.M. McManus D.D. Xanthakis V. Chen M.H. Sullivan L.M. Ingram C. O'Donnell C.J. Keaney J.F. Vasan R.S. Glazer N.L. Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study.J Clin Endocrinol Metab. 2012; 97: E1943-E1947Crossref PubMed Scopus (51) Google Scholar, 20Obuchi A. Adachi H. Enomoto M. Fukami A. Kumagai E. Nakamura S. Yoshimura A. Nohara Y. Nakao E. Umeki Y. Fukumoto Y. Imaizumi T. High plasma fetuin-A levels are associated with metabolic syndrome among males but not females in a Japanese general population.Diabetes Res Clin Pract. 2014; 106: 128-135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 21Xu Y. Xu M. Bi Y. Song A. Huang Y. Liu Y. Wu Y. Chen Y. Wang W. Li X. Ning G. Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese.Atherosclerosis. 2011; 216: 180-186Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar and/or CVD.7Ix J.H. Shlipak M.G. Brandenburg V.M. Ali S. Ketteler M. Whooley M.A. Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study.Circulation. 2006; 113: 1760-1767Crossref PubMed Scopus (277) Google Scholar, 21Xu Y. Xu M. Bi Y. Song A. Huang Y. Liu Y. Wu Y. Chen Y. Wang W. Li X. Ning G. Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese.Atherosclerosis. 2011; 216: 180-186Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar To our knowledge, the present study is the first to examine relations between fetuin-A and MetS in patients with OSA. Neither the presence of nor the number of MetS components was associated with fetuin-A in our experimental cohort. Why our findings differ from others is not clear, but the population characteristics may account for this disparity. Patients with T2DM or CVD were excluded in our cohort, perhaps indicative of a healthier population (despite having OSA) from a cardiometabolic standpoint. That said, the prevalence of MetS in our cohort was similar20Obuchi A. Adachi H. Enomoto M. Fukami A. Kumagai E. Nakamura S. Yoshimura A. Nohara Y. Nakao E. Umeki Y. Fukumoto Y. Imaizumi T. High plasma fetuin-A levels are associated with metabolic syndrome among males but not females in a Japanese general population.Diabetes Res Clin Pract. 2014; 106: 128-135Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 21Xu Y. Xu M. Bi Y. Song A. Huang Y. Liu Y. Wu Y. Chen Y. Wang W. Li X. Ning G. Serum fetuin-A is correlated with metabolic syndrome in middle-aged and elderly Chinese.Atherosclerosis. 2011; 216: 180-186Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar to or greater7Ix J.H. Shlipak M.G. Brandenburg V.M. Ali S. Ketteler M. Whooley M.A. Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study.Circulation. 2006; 113: 1760-1767Crossref PubMed Scopus (277) Google Scholar than that of other cohorts. It is also possible that the presence of OSA may have had an impact, although none of the sleep variables had clear associations with fetuin-A.Focusing specifically on the association of fetuin-A with individual MetS components, the relation between fetuin-A and lipid parameters has appeared to be most consistent. Indeed, only triglycerides and HDL cholesterol among the MetS criteria remained significantly associated with fetuin-A after multivariate adjustment in older patients with CVD.7Ix J.H. Shlipak M.G. Brandenburg V.M. Ali S. Ketteler M. Whooley M.A. Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study.Circulation. 2006; 113: 1760-1767Crossref PubMed Scopus (277) Google Scholar Other studies found the link between triglycerides (rather than HDL cholesterol) and fetuin-A to be more robust, which is supported by our findings and reinforced by our data on VLDL particles. Of clinical relevance is that increased triglyceride concentrations and VLDL particles and decreased HDL cholesterol are predictive of increased atherogenicity.22Chapman M.J. Ginsberg H.N. Amarenco P. Andreotti F. Boren J. Catapano A.L. Descamps O.S. Fisher E. Kovanen P.T. Kuivenhoven J.A. Lesnik P. Masana L. Nordestgaard B.G. Ray K.K. Reiner Z. Taskinen M.R. Tokgozoglu L. Tybjaerg-Hansen A. Watts G.F. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.Eur Heart J. 2011; 32: 1345-1361Crossref PubMed Scopus (905) Google Scholar Thus, it could be argued that elevated fetuin-A concentrations contribute to the increased risk for CVD in subjects with OSA through mechanisms related to dyslipidemia. Earlier studies showed that fetuin-A can bind lipids, forming a lipoprotein-like particle, serve as a carrier protein of free fatty acids, and induce cholesterol efflux from cells.23Kumbla L. Bhadra S. Subbiah M.T. Multifunctional role for fetuin (fetal protein) in lipid transport.FASEB J. 1991; 5: 2971-2975Crossref PubMed Scopus (20) Google Scholar Through its inhibitory effects on the insulin receptor,24Auberger P. Falquerho L. Contreres J.O. Pages G. Le Cam G. Rossi B. Le Cam A. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity.Cell. 1989; 58: 631-640Abstract Full Text PDF PubMed Scopus (273) Google Scholar fetuin-A may also contribute to impaired insulin inhibition of lipolysis, leading to increased free fatty acid release and hepatic VLDL production. The role of fetuin-A in lipid metabolism deserves further investigation.However, this potentially adverse effect of fetuin-A on CVD must be placed within the context of conflicting evidence as to the direction of the relation between fetuin-A and CVD risk. Consistent with our data, Weikert et al6Weikert C. Stefan N. Schulze M.B. Pischon T. Berger K. Joost H.G. Haring H.U. Boeing H. Fritsche A. Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke.Circulation. 2008; 118: 2555-2562Crossref PubMed Scopus (252) Google Scholar described an association between elevated fetuin-A concentrations and myocardial infarction and stroke. Higher fetuin-A was also correlated with greater degree of carotid artery stiffness in healthy subjects, independent of CVD risk factors including lipids.25Mori K. Emoto M. Araki T. Yokoyama H. Teramura M. Lee E. Motoyama K. Koyama H. Shoji T. Inaba M. Nishizawa Y. Association of serum fetuin-A with carotid arterial stiffness.Clin Endocrinol (Oxf). 2007; 66: 246-250Crossref PubMed
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