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BRIEF REPORT |
Kaiser Permanente Division of Research (C.I., G.H., A.S.G., J.C.L.), Oakland, California 94612; Departments of Epidemiology, Biostatistics, and Medicine (C.I., A.S.G.), and Endocrinology and Metabolism Section (J.C.L.), San Francisco General Hospital, Department of Medicine University of California, San Francisco, San Francisco, California 94110; and Stanford Prevention Research Center (J.M.F., S.P.F.) and Departments of Radiology (G.D.R.) and Health Research and Policy (M.A.H.), Stanford University School of Medicine, Stanford, California 94305
Address all correspondence and requests for reprints to: Dr. Carlos Iribarren, Kaiser Permanente, Division of Research, 2000 Broadway, Oakland, California 94612. E-mail: cgi{at}dor.kaiser.org.
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Abstract |
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Objective: The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease.
Design: This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study.
Setting: The study was conducted at an integrated health care delivery system in Northern California.
Participants: Participants included 949 men and women aged 60–69 yr old.
Interventions: There were no interventions.
Main Outcome Measure: The main outcome measure was CAC by multidetector row computed tomography.
Results: In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10–3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89–1.86). However, this association was explained by metabolic risk factors and adiposity measures.
Conclusions: Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.
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Introduction |
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The purpose of this study was to examine, cross-sectionally, the association between plasma leptin and CAC in an ethnically diverse cohort of older adult men and women who were free of clinical cardiovascular disease (CVD).
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Subjects and Methods |
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The Atherosclerotic Disease, Vascular Function and Genetic Epidemiology (ADVANCE) study is a case-control investigation of genetic and nongenetic determinants of coronary artery disease and mode of coronary artery disease presentation. All study participants have been identified and recruited from the membership of Kaiser Permanente of Northern California, a large integrated health care delivery system in the San Francisco Bay Area. Details of recruitment, baseline characteristics and data collection methods are given elsewhere (9). Insulin resistance was estimated using the updated homeostasis model assessment-2 (HOMA-2) model (www.OCDEM.ox.ac.uk). The analysis presented here is based on the older control group, which is the only group in ADVANCE that underwent cardiac multidetector row computed tomography for the quantitation of CAC. The Agatston score was determined using the standard algorithm (10). Interscan or retest variability was determined as the relative error (V1 – V2 / [(V1 + V2)/2]), where V1 is the first value and V2 is the second value on two sequential acquisitions. For the sum of all arteries, the Agatston score had a relative error of 32%. Plasma leptin concentrations were measured by competitive RIA (Linco Research Inc., St. Charles, MO) with within-assay coefficient of variations ranging from 3.4% to 8.3%. The Kaiser Foundation Research Institute and the Stanford University Institutional Review Boards approved all aspects of the study, and all participants gave written informed consent.
Statistical analysis
Bivariate associations between leptin and study covariates were examined using Pearson correlation coefficients for normally distributed continuous variables and Spearman correlation coefficients for nonnormally distributed continuous variables. Bivariate associations with categorical variables were examined using the 
2 test.
Because, as expected, leptin was strongly correlated with body mass index (r = 0.75 and 0.71 in women and men, respectively), all bivariate associations were adjusted for body mass index. To model the multivariate association between leptin and CAC, we used the ordinal logistic regression approach (11). The CAC outcome was expressed as ordinal categories of 0, 1–100, 101–400, and more than 400, as used before in a similar investigation (5). We entered leptin as binary variables representing gender-specific tertiles 2 and 3 vs. tertile 1 and also as a continuous variable (per a 5 ng/ml increment). Four sequential models were considered (see Table 2
). Because both leptin and extent of CAC differ substantially in men and women, all analyses were stratified by gender. We tested the proportionality odds assumption and it was found to be valid in men (score test 2 = 6.4; degrees of freedom = 12; P = 0.89) but violated in women (score test 2 = 33.5; degrees of freedom = 12; P = 0.0008). We therefore also applied an alternative logistic regression approach, namely regression using high CAC thresholds (>100 in women and, for completeness although the proportionality odds assumption was not violated, >400 in men). All analyses were performed using SAS statistical software version 9 (Cary, NC).
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Results |
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). The majority of men and women were white, and smaller proportions were black, Hispanic/Latino, Asian, and other/mixed. Men had higher educational attainment than women, a higher prevalence of former smoking, and a slightly lower prevalence of current smoking. Although no gender differences existed in body mass index, systolic blood pressure, and prevalence of hypertension, waist circumference tended to be larger and diastolic blood pressure and the frequency of diabetes mellitus higher in men than in women. CAC was absent (i.e. calcium score = 0) in 25% of men and in almost 60% of women. The median CAC score was 110 among all men and 2 among all women; the median CAC score among those with a calcium score more than 0 was 169 in men and 38 in women. Self-reported hypothyroidism was more common in women than in men. Although women exhibited higher levels of leptin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein (CRP), men exhibited higher fasting glucose, insulin, and HOMA-2. Triglycerides did not differ significantly between genders. Forty percent of women reported hormone replacement therapy use.
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In ordinal logistic regression adjusting for age, race/ethnicity, and smoking (model 1), the third tertile of leptin (relative to the first tertile) was associated with significantly increased odds of higher CAC [odds ratio (OR) = 1.81, 95% confidence interval (CI), 1.10–3.00] in women but not in men (OR = 1.29; 95% CI = 0.89–1.86) (Table 2
). In the model that included a linear term for leptin, each increment of 5 ng/ml was associated with 1.11 (95% CI, 1.01–1.22) higher odds of higher CAC in women and with 1.13 (95% CI, 0.99–1.30) higher odds of higher CAC in men. However, after adjustment for other risk factors including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, use of cholesterol-lowering agents, hypertension, diabetes, HOMA-2, and CRP (but not for body mass index or waist circumference; model 2), leptin was no longer associated with higher CAC in women. Additional adjustment for body mass index and waist circumference further diminished the strength of association. When we applied logistic regression using a high CAC threshold as the binary dependent variable, consistent but somewhat stronger results (although with wider CIs) were obtained.
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Discussion |
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Our results are at odds with the conclusion of a recent investigation by Reilly et al. (5) among type 2 diabetic subjects, in which leptin was positively associated with CAC even after adjustment for body mass index, waist circumference, CRP, and other measures of subclinical CVD. However, there are notable differences between these two studies. Although our sample comprised mostly nondiabetic persons and had ample representation of women, the sample of Reilly et al. (5) comprised mostly type 2 diabetic men. Furthermore, Reilly et al. used electron-beam computed tomography, whereas we used multidetector row computed tomography for the assessment of CAC. Further research is warranted to shed light on the role of leptin in the development and progression of CAC.
Plasma leptin is known to reflect body fat mass (12) and to be related to insulin sensitivity (13) and inflammatory markers (14). In addition, leptin levels decrease with weight loss (15) and dramatically after bariatric surgery (16). However, the mechanisms responsible for the association between body fat distribution with both leptin and insulin resistance are complex and remain poorly understood.
The role of leptin has expanded from effects on biological processes such as appetite, diabetes, thermogenesis, immune system, and reproduction to a possible direct role in promoting atherosclerosis development. Administration of recombinant leptin to apolipoprotein E-deficient mice resulted in increase in atherosclerosis as measured by lesion surface coverage and in shortened time to occlusive thrombosis after vascular injury (17). In humans, plasma leptin concentrations have been shown to be associated with carotid intimal media thickness, suggesting that leptin may have an unfavorable influence on the development of atherosclerosis. However, in accord with our analysis, the association between leptin and carotid intimal media thickness was not independent of body mass index in a cross-sectional sample of normal-weight and obese men and women (18). Another study has demonstrated an effect of leptin on arterial distensibility measured by high-resolution brachial artery ultrasound (19).
The mechanisms responsible for possible effects of leptin on the vascular wall are far from clear. It had been proposed that leptin induces oxidative stress and expression of monocyte chemoattractant protein-1 in human endothelial cells, and that leptin is able to enhance ADP-induced platelet aggregation and angiogenesis (1, 3). Recently, the presence of leptin receptor has been demonstrated in human atherosclerotic human arteries (20). Relevant to the analysis presented here, leptin had an in vitro direct effect on osteogenic differentiation and enhanced the calcification of vascular cells in the mouse arterial wall (4).
The prospective studies on leptin and CVD risk are mixed. Although elevated leptin was associated with increased risk of CVD events in males and females with familial combined hyperlipidemia (6) and in Scottish men (7), no independent prospective relation between leptin and ischemic heart disease was found in the Quebec Cardiovascular Study (8).
There are limitations in our study to bear in mind. First, the observational cross-sectional design precludes making any causal inferences. Second, the relatively small number of ethnic minority participants enabled us to reliably examine the association between leptin and CAC in ethnically defined strata. Last, because only subjects free of clinical CVD were investigated, results in this study might not be generalizable to the general population.
In sum, although our findings support a role of leptin in vascular calcification (particularly in women), they are consistent with the interpretation that the relation of leptin with CAC may be driven by covariation of leptin with body fat content and related risk factors.
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Footnotes |
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This paper was presented at the 46th Annual Conference on Cardiovascular Disease Epidemiology and Prevention, Phoenix, Arizona, March 2–5, 2006.
First Published Online December 5, 2006
Abbreviations: CAC, Coronary artery calcification; CI, confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; HOMA-2, homeostasis model assessment-2; OR, odds ratio.
Received May 25, 2006.
Accepted November 27, 2006.
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References |
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