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Progression of carotid intima-media thickness and plasma antioxidants: The Los Angeles Atherosclerosis Study

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Progression of carotid intima-media thickness and plasma antioxidants: The Los Angeles Atherosclerosis Study

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Content INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. U M I films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy subm itted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send U M I a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. ProQuest Information and Learning 300 North Zeeb Road, Ann Arbor, M l 48106-1346 USA 800-521-0600 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PROGRESSION OF CAROTID INTIMA-MEDIA THICKNESS AND PLASMA ANTIOXIDANTS THE LOS ANGELES ATHEROSCLEROSIS STUDY by Jing Fan A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (APPLIED BIOSTATISTICS AND EPIDEMIOLOGY) May 2002 Copyright 2002 Jing Fan Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 1411785 __<§) UMI UMI Microform 1411785 Copyright 2003 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor. Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UNIVERSITY O F S O U T H E R N CALIFORNIA TH E GRADUATE SCHOOL UNIVERSITY PARK LOS ANGELES. CALIFORNIA S0007 This thesis, written by Jing Fan under the direction of h Thesis Committee, and approved by all its members, has been pre sented to and accepted by the Dean of The Graduate School, in partial fulfillment of the requirements for the degree of Master of Science D ate— M ax.JQ *..2Q Q X . Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENTS I would like to thank members of my Master’s Thesis Committee, Drs. James H. Dwyer, Stanley P. Azen and Wendy J. Mack, for their advice and suggestions throughout the course of my research and in the preparation of this manuscript. Thanks also go to Lora Whitfield, for her kindly help. I also thank my wonderful husband, Bin Xie, and my parents, for their support and understanding. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ACKNOWLEDGMENTS.................................................................................................ii LIST OF TA BLES............................................................................................................ iv LIST OF FIGURES........................................................................................................... v ABSTRACT.......................................................................................................................vi INTRODUCTION..............................................................................................................1 METHODS......................................................................................................................... 3 Study Population..........................................................................................................3 M easures......................................................................................................................3 Plasma Assays............................................................................................................. 4 Statistical Analysis.....................................................................................................5 RESULTS........................................................................................................................... 6 DISCUSSION...................................................................................................................20 REFERENCES..................................................................................................................25 iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES Table 1. Characteristics of study sample at baseline, from the Los Angeles atherosclerosis Study, 1994-1999(N=563)....................................................... 7 Table 2. Correlation between plasma antioxidant level and carotid IMT, And atherosclerosis risk factors at baseline(N=529)...................................... 8 Table 3. Regression slopes: change in IMT (pm) over 18 months regressed On plasma antioxidants (pmol/L)(n=470).................................................... 10 Table 4. Regression slopes: change in IMT (pm) over 36 months regressed On plasma antioxidants (pmol/L)(n=437).......................................................19 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES Figure 1. The relationship between plasma lutein and IMT change in 1.5 years by s e x ........................................................................................11 Figure 2. The relationship between plasma zeaxanthin and IMT change in 1.5 years by s e x ........................................................................................12 Figure 3. The relationship between plasma P-cryptoxanthin and IMT change in 1.5 years by s e x ........................................................................................13 Figure 4. The relationship between plasma a-carotene and IMT change in 1.5 years by s e x ...................................................................................... 14 Figure 5. The relationship between plasma P-carotene and IMT change in 1.5 years by s e x .........................................................................................15 Figure 6. Plasma antioxidants related with IMT change in 1.5 years......................................................................................................16 Figure 7. Plasma antioxidants unrelated with IMT change in 1.5 years..................................................................................................... 17 V Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT This study investigated associations between plasma antioxidants and progression o f atherosclerosis assessed by common carotid artery intima-media thickness (IMT). Participants were from the Los Angeles Atherosclerosis Study, including 563 subjects (40-60 yrs at entry). Ultrasound examination of IMT and assessment of risk factors for atherosclerosis were performed at baseline, after 1.5 years and 3 years. Fasting plasma antioxidants were measured at baseline. After 1.5 years of follow up, progression of IMT was significantly and inversely related to lutein (p=0.03), P-cryptoxanthin (p=0.008), a-carotene (p=0.008), and zeaxanthin (p=0.007) after controlling for other risk factors. After 3 years, the protective effect of plasma antioxidants on IMT progression were no longer apparent. These findings suggest that higher plasma antioxidant levels are associated with slower progression of early atherosclerosis over a period of 1.5 years, but not over 3 years. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INTRODUCTION It is generally believed that nutrients such as vitamin E, vitamin C, retinol, and carotenoids (including a-carotene, P-carotene, lutein, zeaxanthin, P- cryptoxanthin, and lycopene), function as antioxidants and act as scavengers of free radicals in the human body(Gey, Puska et al. 1991; Rimm, Stampfer et al. 1993; Stampfer, Hennekens et al. 1993; Street, Comstock et al. 1994; Kardinaal, Aro et al. 1995; Azen, Qian et al. 1996; Omenn, Goodman et al. 1996; Iribarren, Folsom et al. 1997; Nyyssonen, Parviainen et al. 1997; Yusuf, Dagenais et al. 2000). The hypothesis that antioxidants play a protective role against cardiovascular disease by inhibiting the damaging activities of oxidized LDL cholesterol has received much attention. Observational evidence from cross-sectional studies, case-control, and cohort, and clinical trials are conflicting. Epidemiological studies have shown high levels of vitamin C, vitamin E and carotenoids in the diet (Rimm, Stampfer et al. 1993; Stampfer, Hennekens et al. 1993), blood(Gey, Puska et al. 1991; Street, Comstock et al. 1994; Nyyssonen, Parviainen et al. 1997), or adipose tissue(Kardinaal, Aro et al. 1995) were associated with decreased cardiovascular disease risk and early atherosclerosis(Iribarren, Folsom et al. 1997). However, intervention studies have found that high doses of vitamin C(Azen, Qian et al. 1996), P-carotene(Omenn, Goodman et al. 1996) or vitamin E(Azen, Qian et al. 1996; Yusuf, Dagenais et al. 2000) intake did not decrease the risk of cardiovascular disease and even increased ischemic heart disease death. l Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The present study was designed to investigate relationships between plasma antioxidant levels and progression of early atherosclerosis in a cohort of healthy women and men. The primary aim of our study was to focus on associations between the progression of carotid intima-media thickness (IMT) monitored over three years with baseline plasma antioxidant levels including ascorbic acid, y- tocopherol, a-tocopherol, lutein, zeaxanthin, P-cryptoxanthin, a-carotene, P- carotene, lycopene, and retinol. Ultrasound assessment of common carotid IMT is a surrogate measurement of intimal thickening and used as a predictor of coronary atherosclerosis and cerebrovascular events (Dwyer, Kwong-Fu et al. 1995; Chambless, Heiss et al. 1997). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. METHODS Study Population The Los Angeles Atherosclerosis Study (LAAS) is a prospective study to investigate relationships between potential etiologic factors and early-stage atherosclerosis. All participants are employees of a large utility company in Los Angeles. They were recruited by letters and follow-up calls at baseline. The baseline survey was conducted between 1995 and 1996. The study sample included 640 eligible women and men aged 40-60 at entry. Exclusion criteria included self- reported history of cardiovascular disease (angina, myocardial infarction, revascularization or stroke), and cancer. Of the remaining 576 subjects, 563 had data on plasma antioxidant concentration and carotid ultrasound images. There were two follow-up examinations, one at 1.5 years later and another after 3 years. The time interval between baseline and follow-up examinations averaged 1.55 years (SD=0.24) at the first follow-up and 3.03 years (SD=0.23) at the second follow-up. All participants signed an informed consent approved by the Institutional Review Board of the Keck School o f Medicine at the University o f Southern California. Measures At each examination, subjects completed a questionnaire regarding information on demographic status, medication use, and health behaviors. Blood pressure in the brachial artery of the right arm, heart rate, body weight and height were also measured. Three 24-hour dietary recalls were collected at the baseline and 1.5-year exams for dietary nutrient intake. Carotid intima-media thickness (IMT), measured by high-resolution B-mode ultrasound with ATL scanner, 3 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. was used as an indication of atherosclerosis. Procedures for image acquisition and processing have been reported previously(Dwyer, Sun et al. 1998). IMT in the left and right carotid arteries were measured in three exams. During the baseline and 3- year follow-up exams, participants were scanned in two body positions (supine and lateral). In the 1.5-year examination, however, the ultrasound image was scanned only in the supine position. All measurements (except two of the 3-day food records and plasma analysis) were conducted during a single examination in a specifically equipped van that was driven to the work site. Plasma Assays Fasting blood samples were collected by venipuncture at baseline (in 1995 and 1996), and were frozen at -70°C. The storage time for these samples was up to two years. Plasma ascorbic acid was analyzed by the high- pressure liquid chromatography (HPLC) method of Kutnink et al (Kutnink, Havvkes et al. 1987). To prevent oxidation during sample storage, an equal volume of 5% or 10% meta-phosphoric acid (MPA) was added before the sample was stored at -70°C. Isoascorbic acid was used as an internal standard to compensate for losses of ascorbic acid during sample processing. Plasma levels of other antioxidants, including y-tocopherol, a-tocopherol, and carotenoids (a-carotene, p-carotene, lutein, zeaxanthin, P-cryptoxanthin, lycopene), and retinol, were determined with the HPLC-based assay derived from the method described by Epler et al (Epler, Ziegler et al. 1993). All measurements were performed at the Heber laboratory (UCLA, California), which participates in the 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. National Cancer Institute/National Institute of Standards and Technology Ascorbic Acid Quality Assurance Program. Serum cholesterol (TG), high-density lipoprotein (HDL) cholesterol and triglycerides (TC) were measured by an autoanalyzer in a laboratory of University of Southern California. Low-density lipoprotein (LDL) cholesterol was estimated for fasting samples with triglycerides <3.95 mmol/L. The formula is LDL = TC - (HDL+0.16xTG) (mmol/L). Statistical Analyses Since distributions of plasma concentrations were skewed, each plasma antioxidant was divided into quintiles. Linear regression models were used to investigate the association between plasma antioxidants and changes of IMT (change at 1.5 years and change at 3.0 years separately). Trend tests across quintiles were computed by regression on the median level of each antioxidant within each sex-specific quintile. Model 1 adjusted for age, sex, and smoking status (current, former and never smoker). The multivariable model (Model 2) further adjusted for BMI, serum cholesterol, HDL-C, systolic blood pressure, current treatment for hypertension and high cholesterol, history of diabetes, ethnicity (White, Black, Latino, Asian, and others), alcohol intake, height, and fasting time. All analyses was conducted by SAS 8.0 (SAS Institute Inc., Cary, N.C.). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. RESULTS The study population was composed of 264 (47%) women and 299 (53%) men, with an average age of 51.6 years for women and 48.7 years for men at baseline. The baseline carotid IMT was 0.68 mm in men and 0.65 mm in women. Most of the participants completed follow-up IMT measurements: 480 (85%) persons at the 1.5-year and 447 (79%) subjects at the 3-year examinations. Additional covariate information was missing for several participants, which yielded a sample size of 470 for the 1.5 years analyses and 437 for the 3 years analyses. Selected characteristics of the 563 subjects at baseline for whom we had serum data are presented in Table I. Table 2 presents the correlation between baseline IMT and plasma antioxidant levels. The relationships between baseline IMT and plasma antioxidant levels were negative for all variables except tocopherol (r =0.08 for y- tocopherol and r=0.03 for a-tocopherol) and retinol (r=0.04). The correlation between baseline IMT and plasma antioxidants was statistically significant for ascorbic acid (r =-0.15), P-cryptoxanthin (r =-0.13), lutein (r=-0.14), a-carotene (r=- 0.12), and P-carotene (r=-0.12). Most plasma antioxidants were significantly associated with plasma cholesterol levels. Plasma antioxidants were also significantly correlated with each other. Besides age, P-cryptoxanthin, a-carotene, P-carotene, and lycopene, other baseline study variables were not significantly different between evaluable samples and inevaluable subjects. Progression of IMT over 1.5 years averaged 0.015 mm/1.5years (SD=0.04). 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Characteristics of stady sample at baseline, from The Los Aageles Atherosclerosis Stady, 1994-1999 (N=563). Characteristics Women Men Total (n=264) (n=299) (n=563) Ethnicity (W hite) * 147(56) 161(54) 308(55) Education (S high school) 45(17) 25(9) 70(12) Current smokers 54(21) 88(29) 142(25) Former smokers 73(28) 98(33) 171(30) Diabetes m ellitus (Yes) 7(3) 9(3) 16(3) M edication for hypertension (Yes) 51(19) 41(14) 92(16) Cholesterol-lowering m edication (Yes) 10(4) 25(8) 35(6) Age at baseline * 51.6±4.3 4 8 .7 1 4 .7 50.114.7 Alcohol intake (gm/day) 3.9 ±8.1 9.4114.4 6.8112.2 Systolic blood pressure (mmHg) 127.8±16.2 129.6112.7 128.7114.5 IMT Measurements Carotid IMT at baseline (m m ) 0.65±0.09 0.6810.10 0.6610.10 IMT change in 1.5 years (m m ) 0.01810.04 0.01310.04 0.0151004 IMT change in 3.0 years (m m ) 0.02810.05 0.03110.05 0.03010.05 Plasma Levels Serum cholesterol (m m ol/L) 5.5110.93 5.6510.99 5.5910.% Serum triglycerides (mmol/L) 1.6611.09 2.0810.14 1.8811.27 Serum HDL-C (mmol/L) 1.6610.37 1.3010.24 1.4710.35 Ascorbic acid (pm ol/L) 31.00121.52 28.54117.86 30.14119.69 Lutein (pmol/1) 0.2910.13 0.2710.12 0.2810.13 Zeaxanthin (pmol/1) 0.0610.04 0.0610.03 0.0610.04 P-cryptoxanthin (pmol/1) 0.0910.07 0.0810.05 0.0910.06 a-carotene (pmol/1) 0.2110.18 0.1610.14 0.1810.17 P-carotene (pm ol/l) 0.8610.79 0.6110.71 0.7310.76 Lycopene (p mo 1 /1 ) 0.7410.70 0.7110.63 0.7310.67 y-tocopherol (pmol/1) 5.2013.55 5.6913.08 5.4613.31 a-tocopherol (pmol/1) 30.62113.95 30.52112.76 30.56113.32 Retinol (pmol/1) 2.1410.79 2.3310.67 2.2410.73 + N (%) * Mean±SD Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission o f th e copyright owner. Further reproduction prohibited without permission. Table 2. Correlation between plasma antioxidant level and carotid IMT, and atherosclerosis risk factors at basellne(n-S29). V it C V lt E Carotenold __________________ Ascorbic add* y-tocopherol a-tocopheroi Lutein Zeaxanthin p-cryptoxanthln a-carotene p-carotene Lycopene Retinol Carotid IM T at baseline •0.1 s' 0.08 0.03 -0.14* •0.04 -0.13* •0.12' -0.12* -0.07 0.04 Currant smokers ■0.07 0.03 0.08 -0.08 0.10* •0.20* •0.20* -0.20* -0.09* •0.08 Former smokers •0.04 0.01 -0.06 0.01 -0.01 0.001 0.003 0.02 •0.004 0.04 Alcohol intake •0.06 0.02 0.08 0.04 0.10* -0.09* 0.009 0.02 0.08 0.09* B M I -0.23* 0.25* •0.03 -0.19* •0.06 •0.19* •0.24* -0.31* -0.18* -0.01 SBP •0.06 0.12* 0.09* -0.10 -0.06 -0.12* -0.19* -0.22* -0.10* 0.12* Plasma Uplde, Total Cholesterol -0.15* 0.32* 0.38* 0.19* 0.21* 0.11* -0.09 -0.08 -0.07 0.23* HDL-cholesterol 0.24* -0.20* -0.006 0.14* 0.07 0.09* 0.24* 0.18* 0.11* 0.03 Triglyceride -0.12* 0.31* 0.42* -0.02 0.06 -0.02 -0.33* -0.39* •0.33* 0.32* LOL-chotesterol(n«487) -0.20* 0.31* 0.30* 0.16* 0.18* 0.10* •0.03 •0.03 0.02 0.15* Plasma Antloxldants Ascorbic Add 1.00 y-tocopherol -0.37* a-tocopherol 0.11* -0.09* Lutein 0.08 0.02 0.25* Zeaxanthin -0.07 0.17* 0.26* 0.64* P-cryptoxanthin 0.17* •0.08 0.18* 0.42* 0.40* 'a-carotene 0.17* -0.24* -0.01 0.20* 0.07 0.37* P-carotene 0.13* -0.32* •0.01 0.25* 0.09* 0.34* 0.85* Lycopene 0.14* -0.20* -0.07 0.15* 0.01 0.28* 0.50* 0.53* Retinol 0.05 0.04 0.04 0.13* 0.10* 0.04 -0.05 -0.10 -0.07* 1.00 P< 0.05 00 Trend tests of mean IMT progression rates over different plasma antioxidant levels by sex were based on linear regression models. When there is no statistically significant difference between males and females, we combined both genders to increase statistical power. Both separated and combined results are presented in Table 3. After adjusting for age, sex and smoking status (Model 1), higher p* carotene (p=0.02), a-carotene (p=0.004), P-cryptoxanthin (p=0.004), and lutein (p=0.007) were associated with lower progression of carotid IMT. For O.lpmol/L increasing of plasma lutein, P-cryptoxanthin, a-carotene, and P-carotene, the mean IMT progression decreased 3.53, 8.40, 3.00, and 0.67pm/yr, respectively. This reverse relationship was also significant for zeaxanthin in males (P= -25.93, p< .001), but not in females. These inverse relationships are depicted in Fig. 1-5 for sex splited and Fig.6 for combined samples. For other antioxidants, y-tocopherol and a- tocopherol did not show any difference in IMT change among quintiles. Associations were in the hypothesized direction (negative) for lycopene, retinol and ascorbic acid as well, but these variables showed no statistically significant IMT change by quintiles(Fig.7). Controlling for other risk factors, including BMI, serum cholesterol, HDL-C, systolic blood pressure, current treatment for hypertension and high cholesterol, history of diabetes, ethnicity, alcohol intake, height, and fasting time (Model 2), did not attenuate these relationships, with the exception of P-carotene (p=0.11). Inverse linear trends remained significant for lutein(p=0.03), P-cryptoxanthin (p=0.008), a-carotene (p=0.008), and zeaxnathin (p= 0.007). With 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission o f th e copyright owner. Further reproduction prohibited without permission. Independent Variable Woman (n»217) Men (n»253) Sex Interaction Combined (n«470) bate* SE p-value bate* SE p-value p-value beta* SE p-valua Lutein Modal 1 -2.73 1.93 0.17 •4.33 1.73 0.012 0.52 •3.53 1,27 0.007 Modal 2 •2.00 1.93 0.31 -3.93 1.73 0.027 0.44 •2.93 1.33 0.026 P-cryptoxanthln Model 1 •5.00 4.00 0.21 •11.87 4.20 0.005 0.23 •8.40 2.87 0.004 Modal 2 •4.07 4.00 0.31 •11.60 4.27 0.007 0.18 •7.80 2.93 0.008 p-carotene Model 1 -0.67 0.33 0.05 -0.67 0.47 0.164 0.99 •0.67 0.27 0.024 Model 2 •0.40 0.33 0.24 •0.53 0.47 0.253 0.79 •0.47 0,27 0.105 Zeaxanthin Model 1 •2.47 6.87 0.72 -25.93 6.20 0.000 0.01 -14.20 4.60 0.002 Model 2 -1.47 7.00 0.63 -24,47 6.60 0.000 0.01 -12.93 4.60 0.007 a-carotene Model 1 •3.33 1.33 0.01 -2.67 1.60 0.097 0.76 •3.00 1.07 0.004 Model 2 •2.60 1.40 0.06 -3.13 1.60 0.056 0.80 -2.87 1.07 0.008 Lycopene Modal 1 -0.33 0.47 0.46 -0.20 0.40 0.656 0.78 -0.27 0.33 0.393 Model 2 •0.07 0.47 0.87 -0.20 0.40 0.602 0.83 •0.13 0.33 0.648 Y-tocopherol Model 1 0.07 0.07 0.41 •0.07 0.07 0.412 0.25 0.00 0.07 0.952 Model 2 0.00 0.07 0.94 •0.07 0.07 0.517 0.61 0.00 0.07 0.708 a-tocopharol Modal 1 0.00 0.00 0.89 0.00 0.00 0.972 0.90 0.00 0.00 0.937 Model 2 0.00 0.00 0.78 0.00 0.00 0.739 0.66 0.00 0.00 0.983 Retinol Model 1 0.20 0.33 0.62 -0.27 0.33 0.398 0.35 -0.07 0.27 0.849 Model 2 0.27 0.40 0.47 •0.40 0.33 0.235 0.17 ■0.07 0.27 0.795 Ascorbic acid Model 1 -39.48 43.87 0.40 13.16 48.25 0.804 0.42 •13.16 30.71 0.691 Model 2 13.16 48.25 0.76 39.46 48.25 0.406 0.67 26.32 35.09 0.416 Model 1 Adjusted for age and smoking status. Modal 2 Adjusted for aga, smoking status, BM f, sarum cholsstorol, HDL-C, systolic blood prassure, traatmant for hypartanslon and high chotestsrol, dlabatas, sthnidty, alcohol Intaka, haight, and fasting tima. * Unit Is (umlMT/yr)/(0.1 pmol/L plasma antlokldant) o s £ c O 4 > £ B 1— i— i— i— i— i— i— i— i— i— i— i— r Hi i m Hi 1 i i o ■ P -110 - « .4 « - O 'rt rt ^ O h o •nttM | c - p <nan ‘< n 3 _l p >nvn | c o « ■ P ‘« « 1 Q_ - o ^ o * m Q ■ O c C O a) c o E C O ro o . c < D a> I a C L co c o co £ C D X I O) IX . O P O P P P P O P p p I I I (ujtu)sjXg i . ui a6ueip j ^ | u Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. change i n 1 .5 years b y sex. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. ? E sex _ 0.0201 0 0 ,“ ■ ^ 0 .0 1 2 1 a > ? (0 women men 0. 0001 J Z o 0. 0001 h- 5 0. 0041 o 0 o 0 0 0 o o o o o o o o o o o a o o i 1 i 1 0 S 4 4 S 0 7 0 0 0 1 1 4 5 2 0 * 0 7 8 4 3 1 09 Plasma Zeaxanthin (mmol/L) Fig2. The relationship between plasma Zeaxanthin and IMT change in 1.5 years by sex. N > Reproduced with permission o f th e copyright owner. Further reproduction prohibited without permission. sex 2 ^ women 0 .0 1 BB x U ) men 0 .0 0 4 7 0 .0 0 0 7 0 .0 0 3 3 0 .0 0 7 3 '0.0112 o » o o 0 0 0 o o o o a 4 o & r o o o o B o 7 7 D B 0 « 0 1 1 7 1 3 O 1 A 3 1 A 7 1 7 O 1 « 3 Plasma b-cryptoxanthin (mmol/L) Fig3. The relationship between plasma b-cryptoxanthin and IMT change in 1.5 years by sex. u > $ 0 1 o' N 1 o * ° * E o £ a £ 0 5 - i (I w A ° 0 < n (0 N (0 0 i m 1 Q. 4 4 0 o o' $ M • o o o o o o M ‘ § ! § S 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (ujuj)sMgi, u; a6ueip1W I o 6 X ' 14 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Fig4. T h e relationship between plasma a-carotene a n d IM T change i n 1 .5 years b y sex. Reproduced with permission o f th e copyright owner. Further reproduction prohibited without permission. sex women men 0. 01 A S 0 .0 0 7 0 0 .0 0 0 . 1 0 0 .3 3 Plasma b-carotene (mmol/L) Fig5. The relationship between plasma b-carotene and IMT change in 1.5 years by sex. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. 0.03 Zeaxanthin b-cryptoxanthin a-carotene Lutein 0.025 £ (0 & 0.02 in - 0.015 d ) S' I 001 h* 1 0.005 2 3 1 4 5 I Quintiles of Plasm a antioxidants Fig6. Plasm a antioxidants related with IMT change in 1.5 years (adjusted age, sex, and smoking status) O n I i m C M i n o o o 3 I 2 > I in < D I 1 1 iS C O Jf * i _ to , J C D 03 d ■ g j c o C C D 3 O) g « C D TJ § C D 1 C O C O O) 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. O.lpmol/L increasing in plasma lutein, (i-cryptoxanthin, a-carotene, and zeaxanthin, the progression of IMT decreases 2.93, 7.80, 2.87, and 12.93pm/yr, respectively. The mean progression of IMT over 3 years was 0.030 mm/3 years (SD=0.05). The relations between change o f IMT in 3.0 years and plasma antioxidants are presented in Table 4. In contrast to the study hypothesis, the results were not statistically significant. A borderline protective effect was found for plasma zeaxanthin in males (p=0.052) and a-carotene in females (p=0.05). All other plasma antioxidants provided protective but non-significant effects in both models. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 4 Regression slopes: chsngs In IM T (urn) o v r 36 months regressed on plasma antloxldanta (umol/L)(nM37). Women (n»200) Men (n»237) Sex Interaction Combined (n«437) Independent veriable beta* SE p value beta* SE p value p value beta* SE P value Lutein Model 1 -0.10 1.23 0.93 -1.27 0.97 0.195 0.46 -0.70 0.80 0.381 Model 2 0.20 1.23 0.88 -0.73 1.03 0.476 0.18 -0.27 0.80 0.737 P-cryptoxanthin Model 1 -1.S7 2.43 0.52 -3.33 2.53 0.188 0.61 -2.47 1.77 0.163 Model 2 -0.20 2.47 0.93 -2.07 2.60 0.424 0.59 -1.13 1.80 0.523 p-carotene Model 1 -0.10 0.20 0.63 0.10 0.27 0.698 0.55 0.00 0.17 0.969 Model 2 0.10 0.20 0.63 0.30 0.27 0.288 0.54 0.20 0.17 0.253 Zeaxanthin Model 1 3.13 3.67 0.39 -7.37 3.77 0.052 0.04 -2.10 2.63 0.423 Model 2 2.90 3.67 0.43 -6.03 4.10 0.14 0.09 -1.57 2.73 0.567 a— carotene Model 1 -1.60 0.80 0.05 -0.13 0.93 0.877 0.23 -0.87 0.60 0.156 Model 2 -0.93 0.83 0.25 •0.20 0.90 0.836 0.52 -0.57 0.60 0.353 Lycopene Model 1 -0.03 0.27 0.87 0.33 0.23 0.166 0.29 0.17 0.20 0.415 Model 2 0.17 0.27 0.52 0.30 0.23 0.214 0.73 0.23 0.17 0.19 Y-tocopherol Model 1 0.07 0.03 0.22 0.03 0.03 0.356 0.8 0.03 0.03 0.129 Model 2 0.00 0.03 0.81 0.00 0.03 0.826 0.98 0.00 0.03 0.748 a-tocopherol Model 1 0.00 0.00 0.85 0.00 0.00 0.643 0.84 0.00 0.00 0.647 Model 2 0.00 0.00 0.67 0.00 0.00 0.491 0.84 0.00 0.00 0.426 Retinol Model 1 0.10 0.20 0.62 •0.03 0.17 0.808 0.6 0.03 0.13 0.837 Model 2 0.13 0.20 0.55 •0.17 0.20 0.372 0.28 •0.03 0.13 0.87 Ascorbic acid Model 1 -24.13 26.32 0.36 -21.93 28.51 0.442 0.95 •24.13 19.74 0.235 Model 2 13.16 28.51 0.64 •2.19 28.51 0.938 0.68 4.39 19.74 0.79 Model 1 Adjusted for age and smoking status. Model 2 Adjusted for age, smoking status, B M I, serum cholesterol, HDL-C, systolic blood pressure, treatment for hypertension and high cholesterol, diabetes, ethnicity, alcohol intake, height, and testing time. * Unit is (pmlMT/yr)/(0.1 pmot/L plasma antioxidant) S O DISCUSSION The main findings presented here were that higher plasma levels of carotenoids, such as a-carotene, p-carotene, lutein, zeaxanthin, and P-cryptoxanthin at baseline were associated with significantly decreased progression of carotid IMT over 1.5 years. Other than P-carotene, this association with carotenoids was not explained by the confounding with other atherosclerosis risk factors. Other antioxidants, including lycopene, retinol, ascorbic acid, y-tocopherol, and a- tocopherol were not significant associated with IMT change. In contrast to the 1.5- year follow up, none of these antioxidants were associated with carotid IMT change measured over 3 years. Plasma antioxidant concentrations are determined by both the amount of antioxidants in meals and supplement intake. Circulating antioxidant levels in fasting samples may reflect a long-term variation in vegetable, fruit or supplement intake. Carrots and dark green leafy vegetables such as spinach, kale, squash, broccoli, and collards are rich in a-carotene, p-carotene, zeaxanthin and lutein. P-cryptoxanthin, is primary found in papaya, red pepper and yellow-colored fruits such as persimmons, mangos, and tangerine. The results from the present study suggest that higher intake of vegetables and fruits containing these antioxidants, or supplement would have a protective effect on cardiovascular diseases. Results from epidemiological investigations concerning blood antioxidant levels and atherosclerotic diseases are conflicting and the data about plasma 20 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. antioxidants and progression of early atherosclerosis are limited. Our group has already reported the protective effect o f lutein on the progression of carotid IMT at 1.5-year follow up. This finding motivated the coculture and mouse model experiments. Pretreatment of the coculture cells with lutein as low as lOnmol/L inhibited the inflammatory response o f monocytes to LDL trapped in the artery wall (reduced monocyte migration 8-fold). In the mouse models, lutein supplementation reduced lesion size 43% in LDL receptor-null mice (p=0.02) and 44% in apoE-null mice (p=0.009) (Dwyer, Navab et al. 2001). A cross-sectional nested case-control study from the ARIC study also used carotid IMT as a measure of asymptomatic atherosclerosis. Cases (n=231) were defined as the subjects exceeded approximately the 90th percentile of IMT of the cohort, and control subjects (n=231) were below the 75th percentile of IMT for all artery segments. They reported that carotid IMT had a significantly inverse relationship with serum P-cryptoxanthin (OR=0.76, 95%CI: 0.61,0.95) and lutein plus zeaxanthin (OR=0.79, 95%CI: 0.59,0.95). Carotid IMT was not significantly related to other serum antioxidants including a-carotene, p-carotene, lycopene, retinol, and a-tocopherol(Iribarren, Folsom et al. 1997). Another nested case-control study measured the relationship between myocardial infarction risk and four serum carotenoids (P-carotene, lycopene, lutein, and zeaxanthin), and a-tocopherol. There was a significantly higher risk of myocardial infarction for persons who were in lowest quintile of P-carotene compared to those in highest quintile (OR =2.23). The trend test for increasing myocardial infarction with decreasing levels of p-carotene was 21 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. significant (P=0.02), and a suggestive trend with decreasing levels of lutein (P trend =0.09, lowest quintile vs highest OR =1.17) (Street, Comstock et al. 1994). In eastern Finland, a five-year prospective study indicated that the plasma vitamin C deficiency at baseline was a risk factor for acute myocardial infarction(Nyyssonen, Parviainen et al. 1997). However, a population-based case-control study using angina pectoris as an end point reported that plasma vitamin E was inversely related with angina pectoris, but there was no significant inverse association between angina and plasma carotene, or vitamin C (Riemersma, Wood et al. 1991). The MRFIT study indicated that there was no association between baseline serum lipid soluble antioxidants (carotenoids, retinol, y-tocopherol, a-tocopherol) and the risk of coronary heart disease death or nonfatal myocardial infarction after approximately 20 years follow-up(Evans, Shaten et al. 1998). The strength o f our study is that we focused on the progression of IMT in asymptomatic individuals for 3 continuous years. Carotid IMT is an established measure of early stage atherosclerosis and is a noninvasive predictor of future CHD incidence (Chambless, Heiss et al. 1997). There are few data regarding the progression of early atherosclerosis. In a high-risk group (middle-aged), the progression rate of atherosclerosis is not the same for everybody. To define which factors will influence the development of atherogenesis will give clues for primary prevention of events of cardiovascular disease. Following a healthy cohort for about 3 years and monitoring their IMT changes may provide insights into the progression of preclinical atherosclerosis in middle-aged people. 22 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Contrary to our expectations, plasma antioxidant levels were not associated with carotid IMT change over 3 years. We recognize that there are some sources of potential bias in our study. First, using baseline plasma antioxidant levels as a predictor for progression of atherosclerosis is based on an assumption that no significant change occurred in dietary habits or supplement use during the subsequent 1.5 and 3 years. Usually, dietary behavior is stable for middle-aged people from year to year. However, it is still possible for individuals to change their diet. For example, the development of hypertension or high cholesterol could result in major alterations in dietary habits. The effect of dietary change might not be obvious in a short time such as 1.5 years but may become more apparent in 3 years. Baseline plasma samples cannot assess this potential dietary change during follow- up. Continuous blood measurements in 3 years follow-up or later are necessary to avoid this bias. Second, in addition to low dietary and supplement intake of antioxidants, inflammation caused by atherosclerosis can also reduce the plasma level of antioxidants. Langlois M. and his colleagues reported that vitamin C concentrations were lower in intermittent claudicant patients. This low concentration is negatively correlated with severity o f peripheral arterial disease and serum C- reactive protein (CRP) (r= -0.742, p<0.0001), which is a biomarker of inflammation(Langlois, Duprez et al. 2001). Inflammation may play an important rule in determining concentrations of plasma antioxidants. The interaction between diet and inflammation might mask the relationship between a healthy diet and the progression of early atherosclerosis. 23 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In summary, this study provides evidence for an inverse association between plasma levels of antioxidants, particularly P-cryptoxanthin, a-carotene, zeaxanthin and lutein, with progression of carotid IMT over 1.5 years. These findings suggest that plasma antioxidant levels (presumably biomarkers of food and supplement intake) may be important in early stages of atherogenesis. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES Azen, S. P., D. Qian, et al. (1996). “Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering.” Circulation 94(10): 2369-2372. Chambless, L. E., G. Heiss, et al. (1997). “Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: The Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993.” American Journal of Epidemiology 146(6): 483-494. Dwyer, J. H., H. Kwong-Fu, et al. (1995). Reproducibility of carotid intima-media thickness measured with a low cost and mobile ultrasound system. First International Symposium on Vascular Wall Thickening, Paris. Dwyer, J. H., M. Navab, et al. (2001). “The oxygenated carotenoid lutein and progression of early atherosclerosis. The Los Angeles Atherosclerosis Study." Circulation 103: 2922-2927. Dwyer, J. H., P. Sun, et al. (1998). “Automated intima-media thickness: The Los Angeles Atherosclerosis Study.” Ultrasound in Medicine and Biology 24(7): 981 - 987. Epler, K. S., R. G. Ziegler, et al. (1993). “Liquid chromatographic method for the determination o f carotenoids, retinoids and tocopherols in human serum and in food.” JChrom 619: 37-48. Evans, R. W., B. J. Shaten, et al. (1998). “Prospective association between lipid soluble antioxidants and coronary heart disease in men. The Multiple Risk Factor Intervention Trial.” American Journal of Epidemiology 147(2): 180-6. Gey, F. K., P. Puska, et al. (1991). “Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology.” Am J Clin Nutr 53: 326S-334S. Iribarren, C., A. R. Folsom, et al. (1997). “Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis.” Arterioscler Thromb Vase Biol 17(6): 1171-1177. Kardinaal, A. F. M., A. Aro, et al. (1995). “Association between beta-carotene and acute myocardial infarction depends on polyunsaturated fatty acid status: the EURAMIC Study.” Arteriosclerosis, thrombosis, and vascular biology 15(6): 726- 732. 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Kutnink, M., W. C. Hawkes, et al. (1987). “An internal standard method for the unattended high-performance liquid chromatographic analysis of ascorbic acid in blood components.” Anal. Biochem. 166:424-430. Langlois, M., D. Duprez, et al. (2001). “Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis.” Circulation 103(14): 1863-8. Nyyssonen, K., M. T. Parviainen, et al. (1997). “Vitamin C deficiency and risk of myocardial infarction: prospective study of men in eastern Finland.” British Medical Journal 314(7081): 634-638. Omenn, G. S., G. E. Goodman, et al. (1996). “Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.” New England Journal of Medicine 334( 18): 1150-1155. Riemersma, R. A., D. A. Wood, et al. (1991). “Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene.” Lancet 337(8732): 1-5. Rimm, E. B., M. J. Stampfer, et al. (1993). “Vitamin E consumption and the risk of coronary heart disease in men.” New England Journal of Medicine 328(20): 1450- 1456. Stampfer, M. J., C. H. Hennekens, et al. (1993). “Vitamin E consumption and the risk of coronary disease in women.” New England Journal of Medicine 328: 1444- 1449. Street, D. A., G. W. Comstock, et al. (1994). “Serum antioxidants and myocardial infarction: Are levels o f carotenoids and alpha-tocopherol risk factors for myocardial infarction?” Circulation 90(3): 1154-1161. Yusuf, S., G. Dagenais, et al. (2000). “Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.” N Engl J Med 342(3): 154-60. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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Creator Fan, Jing (author)

Core Title Progression of carotid intima-media thickness and plasma antioxidants: The Los Angeles Atherosclerosis Study

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

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Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-294355

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