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Adiponectin and Risk of Coronary Heart Disease in Older Men and Women

Departments of Medicine and Public Health (J.R.K.), Weill Medical College of Cornell University, New York, New York 10065; Division of Endocrinology (J.I.B.), Kaiser Permanente of Georgia, and Division of Endocrinology, Emory University School of Medicine, Atlanta, Georgia 30322; Department of Epidemiology (L.H.K.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; and Division of Cardiology (J.S.G.), University of Maryland Medical Center, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Dr. Jorge Kizer, Box 222, Weill Cornell Medical Center, 525 E. 68th Street, New York, New York 10065. E-mail: jok2007{at}med.cornell.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Despite established insulin-sensitizing and antiatherogenic preclinical effects, epidemiological investigations of adiponectin have yielded conflicting findings, and its relationship with coronary heart disease (CHD) remains uncertain.

Objective: Our objective was to investigate the relationship between adiponectin and CHD in older adults.

Design, Setting, and Participants: This was a case-control study (n = 1386) nested within the population-based Cardiovascular Health Study from 1992–2001. Controls were frequency-matched to cases by age, sex, race, subclinical cardiovascular disease, and center.

Main Outcome Measures: Incident CHD was defined as angina pectoris, percutaneous or surgical revascularization, nonfatal myocardial infarction (MI), or CHD death. A more restrictive CHD endpoint was limited to nonfatal MI and CHD death.

Results: Adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. After controlling for matching factors, adjustment for waist to hip ratio, hypertension, smoking, alcohol, low-density lipoprotein cholesterol, creatinine, and leptin revealed a modestly increased risk of incident CHD with adiponectin concentrations at the upper end [odds ratio = 1.37 (quintile 5 vs. 1–4), 95% confidence interval 1.02–1.84]. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD (odds ratio = 1.69, 95% confidence interval 1.23–2.32). The findings were not influenced by additional adjustment for weight change, health status, or cystatin C, nor were they abolished by adjustment for potential mediators.

Conclusions: This study shows an association between adiponectin and increased risk of first-ever CHD in older adults. Further research is needed to elucidate the basis for the concurrent beneficial and detrimental aspects of this relationship, and under what circumstances one or the other may predominate.

	Introduction

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Since the identification of adiponectin as the most abundant factor secreted by adipocytes, the physiological role of this peptide has attracted intense scrutiny (1). Adiponectin correlates negatively with adiposity, and bears an inverse relationship with insulin resistance, atherogenic dyslipidemia, and inflammatory markers (2). Laboratory studies of adiponectin have demonstrated direct insulin-sensitizing actions, which accords with epidemiological evidence of a strong link between low circulating adiponectin and incident diabetes (3). These insulin-sensitizing properties suggest that reduced adiponectin concentration may underlie the heightened vascular risk associated with obesity and the metabolic syndrome.

Beyond its metabolic actions, there is considerable preclinical evidence that adiponectin exerts direct antiatherosclerotic and cardioprotective effects (4). Nevertheless, epidemiological studies evaluating the role of adiponectin in cardiovascular disease have been contradictory. Among middle-aged adults, one population-based study found a significant inverse relationship with incident coronary heart disease (CHD) (5), but this has not been reproduced in subsequent investigations (6, 7, 8). By contrast, prospective studies of patients with heart failure (9), renal insufficiency (10), or CHD (11, 12) have reported greater adverse outcomes with higher circulating adiponectin. Such increased risks have been attributed to the higher adiponectin levels associated with heart failure-related wasting (9) or impaired renal function (10), which would confound the adipokine’s proposed beneficial effects.

In older adults, population-based studies assessing CHD have been no more consistent, with findings of a race-based interaction in one (13), a significantly protective relationship in another (14), and no significant overall association in a third (15). These results contrast with those for mortality outcomes, for which an increased adiponectin-associated risk of cardiovascular and all-cause death has been independently documented (15, 16), even among predominantly middle-aged cohorts (17).

It is possible that different age, sex, and race-ethnic distributions, or differences in extent of subclinical cardiovascular disease, could account for the lack of consistency in reported findings. In the present report, we investigated the association between adiponectin and CHD in a case-control study nested within a well-characterized cohort of older adults, in which we undertook matching for the aforementioned risk factors, including the preeminent predictor of incident CHD, subclinical disease (18), to minimize their potential influence on the relationship under study.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study population and procedures

The Cardiovascular Health Study (CHS) is a population-based longitudinal survey of older adults, methods for which have been reported in detail elsewhere (19). In brief, participants consisted of noninstitutionalized, community dwelling adults aged 65–100 yr sampled from Medicare eligibility lists, and recruited from four field centers in the United States. An original cohort of 5201 individuals was recruited in 1989–1990, with a second cohort of 687 African-Americans recruited in 1992–1993, yielding a total of 5888 participants. All subjects provided written informed consent before participation.

Participants underwent extensive evaluation in 1989–1990 and again in 1992–1993. Evaluation comprised detailed history, physical examination, and laboratory testing. Participants reported to CHS field centers after an 8- to 12-h fast. Blood collection, processing, and storage were conducted following quality assurance protocols (20). Laboratory measurements included serum creatinine, fasting serum glucose and insulin, lipid subfractions, C-reactive protein, and fibrinogen (20, 21). Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation. Cystatin C was measured in stored serum (22). Subjects were also evaluated for subclinical disease with electrocardiography, carotid ultrasound (23), measurement of ankle-brachial index (24), and Rose questionnaire for angina and claudication.

Because of limited availability of blood samples from 1989–1990, the present case-control study was nested within the 3857 participants free of prevalent cardiovascular disease who completed the 1992–1993 examination. Cases consisted of 282 men and 322 women with analyzable samples who experienced a CHD event through June 2001. Of these events, 133 and 122 were nonfatal myocardial infarction (MI), 51 and 64 were fatal CHD, and the remainder nonfatal CHD, in men and women, respectively. Controls were participants free of incident CHD who were frequency matched to cases in a 1.3:1 ratio by the variables age, sex, race-ethnicity, subclinical disease status, and center.

Definitions

Diabetes was defined by a fasting glucose of more than or equal to 126 mg/dl, or by treatment with oral hypoglycemics or insulin. The homeostasis model assessment insulin resistance (HOMA-IR) index was also calculated (25). Meaningful weight change was defined as more than a 10-lb increase or decrease in the measured value between the 1989–1990 and 1992–1993 examinations, or based on self-report for the past year in a questionnaire that also ascertained whether such change was attributable to illness, surgery, or medication. In the latter case, weight loss was classified as "involuntary." Subclinical disease was defined as having one or more of the following in the absence of clinical cardiovascular disease: internal carotid wall thickness more than the 80th percentile, common carotid wall thickness more than the 80th percentile, carotid stenosis more than 25%, major electrocardiogram changes (24), positive Rose questionnaire, or ankle-brachial index less than 0.9.

Cardiovascular events

Prevalent clinical cardiovascular disease was defined as MI, angina pectoris, heart failure, peripheral arterial disease, stroke, or transient ischemic attack. At the 1992–1993 examination, clinical cardiovascular disease was ascertained by combining the CHS questionnaire, physical examination, electrocardiography, medical record review, and physician confirmation (26).

The outcome of interest, any CHD event, is a composite of nonfatal events (MI, angina pectoris, coronary bypass surgery, or percutaneous revascularization) and fatal events (MI, sudden cardiac death, and procedure related death), as previously defined (19, 26, 27). A more restrictive CHD outcome was defined as nonfatal MI and fatal CHD. As detailed elsewhere (27), follow-up surveillance and ascertainment entailed interviews of participants biannually and examinations annually at each center. Potential incident events, hospitalized and outpatient, and all deaths were investigated by review of medical records and discharge summaries. These were initially classified by local physicians at the field centers, with final classification determined by a CHS committee using standardized criteria (19, 27).

Measurement of adipokines

Adipokine testing was performed at the CHS Core Laboratory in 2005. Measurements made on serum stored at –70 C after venipuncture in 1992–1993 were blinded to case-control status. Adiponectin was measured using an ELISA (R&D Systems, Inc., Minneapolis, MN). Intraassay and interassay coefficients of variation are 2.5–4.7% and 5.8–6.9%, respectively. Comparison of this assay to a RIA (LINCO Research, Inc., St. Charles, MO) revealed excellent correlation (R² = 0.95), but higher values for the ELISA (slope = 2.19). Leptin was also measured using an ELISA. Intraassay and interassay coefficients of variation are 3.0–3.3% and 3.5–5.4%, respectively.

Statistical analysis

Comparisons of categorical and continuous variables between cases and controls used the ² and Student’s t test, respectively, whereas those of continuous variables across more than two strata applied ANOVA with linear contrasts. Age-adjusted partial correlation coefficients were computed for adiponectin and various covariates. Positively skewed variables were log transformed in all analyses.

We first investigated the relationship between adiponectin and CHD by generating sex-specific quintiles based on the distribution of adiponectin in the control group. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs). Adjusted models were constructed with addition of covariates capable of confounding the association between adiponectin and CHD. Covariates included the matching factors age, sex, race (Black/other), subclinical disease (yes/no), and center; the atherosclerosis risk factors waist to hip ratio, systolic blood pressure, the antihypertensive medication (yes/no), LDL-cholesterol, smoking (current vs. ever/never), alcohol consumption (none, one to six, seven to 13, 14 drinks per week), log creatinine, log leptin (29), and, in women, estrogen replacement (yes/no); and the potential mediators diabetes (yes/no), log high-density lipoprotein (HDL) cholesterol, log triglycerides, log C-reactive protein, fibrinogen, and, in individuals not receiving hypoglycemic therapy, log HOMA-IR. Additional models examined the impact of measured or self-reported weight change in the past 3- or 1-yr period, respectively, using indicator variables for weight gain and weight loss vs. stable weight, self-reported health status (poor or fair vs. good, very good, or excellent), and log-cystatin C instead of log creatinine. Tests for trend across adiponectin quintiles relied on an ordinal variable with levels corresponding to the median for each quintile. First-order tests for interaction included cross-product terms between this ordinal variable and covariates. All analyses were performed with SPSS Inc., version 12.0 (Chicago, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 presents the clinical characteristics of the study cohort. Among both men and women, cases and controls exhibited similar values for matching factors, but cases had higher body mass index, waist to hip ratio, systolic blood pressure, triglycerides, cystatin C, C-reactive protein, and leptin, as well as lower HDL-cholesterol. Male cases were more frequently on antihypertensive therapy than controls, whereas female cases had more diabetes, higher HOMA-IR, and were more often on oral hypoglycemic therapy than corresponding controls.

View larger version (9K): [in this window] [in a new window]   FIG. 1. Relationship between weight stability or change (>10 lb) and adiponectin concentration, based on measured weights 3 yr apart or self-reported weight change in the past year.

View larger version (30K): [in this window] [in a new window]   FIG. 2. Sex-specific quintiles (Qs) of adiponectin and risk of CHD events. Model 1 contains age, sex, race, subclinical disease, and clinic. Model 2 includes covariates in model 1 plus waist to hip ratio. Model 3 shows covariates in model 2 plus systolic blood pressure, LDL-cholesterol, current smoking, alcohol consumption, serum creatinine, and leptin. Model 4 contains covariates in model 3 plus health status and measured weight loss or gain more than 10 lb in past 3 yr.

View larger version (27K): [in this window] [in a new window]   FIG. 3. Sex-specific quintiles (Qs) of adiponectin and risk of nonfatal MI and fatal CHD. Models are as in Fig. 2.

Of note, adjustment for proposed mediators such as diabetes, HDL-cholesterol, triglycerides, C-reactive protein, and fibrinogen led to a significant relation for the highest vs. the lowest quintile of adiponectin and CHD events (OR = 1.77, 95% CI 1.1.6–2.68). In the case of nonfatal MI and fatal CHD, the relationship became stronger [OR (quintile 5 vs. 1) = 2.19, 1.37–3.48]. Similar results were obtained for either endpoint upon adjustment for HOMA-IR. However, because adjustment for potential mediators can lead to biased estimates of effect (28), these findings are not considered for hypothesis-testing purposes.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this case-control study nested within a community based cohort of older adults, increased adiponectin levels did not exhibit a significant protective relationship with future risk of CHD. Instead, there was an increased adjusted risk of CHD associated with the highest quintile of adiponectin, an association that became stronger when the focus was on the more stringent outcome of nonfatal MI and fatal CHD.

The present findings come in the setting of disparate epidemiological observations, which in older adults have been characterized by conflicting results with regard to CHD events and all-cause mortality. In a study evaluating the relationship of adiponectin with CHD among older Americans of both sexes, there was a significant interaction by race (13). After adjustment for confounders and mediators, an initially significant inverse relationship in whites became nonsignificant, whereas in Blacks the association was found to be direct and statistically significant. Another U.S. study found a significant protective relationship between adiponectin and nonfatal incident CHD only in men, but no significant overall relationship with incident CHD. However, there was an increased adjusted risk of cardiovascular and all-cause mortality with higher adiponectin concentration (15). By contrast, a study of older Swedish men did find adiponectin to be associated with a significant reduction in overall CHD risk (14). Most recently, an investigation in older British men confirmed an increased risk of cardiovascular and all-cause mortality with higher adiponectin (16), regardless of heart failure status, self-reported weight loss, and renal function (16).

Our findings, which are based on the largest number of first-incident CHD events in an elderly cohort to date, are at odds with prior reports of a protective association with CHD, whether overall (14) or limited to nonfatal events (15). They also contrast with previous null results regarding fatal and nonfatal CHD (13, 15), while failing to confirm a previously noted interaction by race (13).

That the association emerged only after adjustment for covariates, principally waist to hip ratio (or body mass index), points to confounding by measures of adiposity in our sample. Because such measures were negatively correlated with adiponectin but positively correlated with an adverse metabolic profile, the greater adiposity in cases than controls effectively masked the association between adiponectin and higher CHD risk. Notably, this relationship persisted after adjustment for other factors that can influence the adiponectin-CHD relationship, especially in the elderly, including measured weight change, self-reported health status, and different measures of renal function. Thus, the findings provide compelling evidence that previously reported (15, 16) direct associations of increasing adiponectin with cardiovascular and all-cause mortality in the elderly extend to coronary events in particular.

How does one reconcile the metabolic and vascular benefits of adiponectin documented in laboratory studies, and the protection mainly in middle-aged populations against incident diabetes and, potentially, CHD events, with the heightened risk of CHD or mortality in older adults observed here or reported elsewhere? One potential explanation is provided by the loss of fat-free mass that characterizes aging (30). Such wasting of skeletal muscle or "sarcopenia" is a recognized determinant of mortality in older adults (31). Therefore, the usual inverse relationship between adiponectin and body weight, which in younger adults is predominantly determined by changes in diet and lifestyle, can in older adults reflect frailty and physical decline, thereby confounding the adiponectin association with outcome. Nevertheless, the increased risk of CHD observed for adiponectin in this study was not modified by antecedent weight change, nor was there an appreciable influence of self-reported health status, suggesting that physical decline does not account, at least in a major measurable way, for the results.

Another consideration would be the phenomenon of "adiponectin resistance," which has been advanced to explain paradoxical increases in adiponectin-associated adverse outcomes (32). Yet the magnitude of baseline correlations with insulin sensitivity and inflammatory markers observed here argues against this possibility. An alternative proposition is that adiponectin is produced in response to vascular inflammation to counter the atherosclerotic process (33). According to this premise, the adipokine would serve as a marker of disease severity in patients with clinical CHD or older adults with subclinical cardiovascular disease, but not to the same degree in younger populations free of prevalent CHD. However, we did not find adiponectin concentration to be higher in participants with than without subclinical disease at baseline or evidence of a significant interaction by subclinical disease status. This leaves the possibility that, in addition to its salutary actions, adiponectin has direct harmful effects, which could be more operative in the elderly. Indeed, adiponectin has increased energy expenditure through direct actions in the central nervous system in mice (34), an effect that, if present in humans, could be particularly deleterious in older adults by potentially accelerating sarcopenia.

It bears noting that adiponectin circulates in human plasma as covalently bound multimers of various molecular weights (3). Molecular signaling properties differ among adiponectin multimers, and it is the high-molecular weight (HMW) isoform that appears to be the most potent activator of insulin-sensitizing (3) and antiatherogenic (35) pathways. This raises the possibility that the heterogeneous epidemiological findings reported thus far for total adiponectin could relate to different proportions of HMW adiponectin. In keeping with this premise, some (36, 37), but not all (38), clinical studies have reported stronger inverse associations for HMW than total adiponectin with insulin resistance and CHD. Interestingly, the reverse was documented in patients with heart failure, in whom total adiponectin was the stronger predictor of adverse outcome (39).

Several limitations deserve mention. Only individuals surviving until the 1992–1993 examination free of cardiovascular disease were included in the study sample. Yet because survivorship would apply equally to cases and controls, this would influence the external validity of the findings, but not their internal validity. Second, the present study did not have concurrent measures of body composition and was unable to assess directly the fraction of fat-free mass (sarcopenia) present at baseline. Future studies of older adults will need to examine the extent to which body composition influences adiponectin-related outcomes. Finally, we did not measure the HMW adiponectin isoform (37), further assessment of which will be necessary to elucidate the clinical effects of this peptide.

In conclusion, this study shows that, despite documented preclinical cardiometabolic benefits and favorable cross-sectional clinical associations, elevated concentrations of circulating adiponectin are associated with a significantly increased risk of incident CHD in older adults. These findings suggest that adiponectin harbors both salutary and harmful properties, the understanding of which could be advanced by additional attention to the adipokine’s complex multimer distribution and, in the elderly, the potential role of altered body composition.

	Footnotes

 
This work was supported by a Clinically Applied Research Grant from the American Heart Association’s Heritage Affiliate and by Grant K23 HL070854 from the National Heart, Lung, and Blood Institute (to J.R.K.), and by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke.

A full list of participating Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org.

Disclosure Statement: The authors have no relevant financial conflicts of interest to disclose.

First Published Online July 1, 2008

For editorial see page 3299

Abbreviations: CHD, Coronary heart disease; CHS, Cardiovascular Health Study; CI, confidence interval; HDL, high-density lipoprotein; HMW, high-molecular weight; HOMA-IR, homeostasis model assessment insulin resistance; LDL, low-density lipoprotein; MI, myocardial infarction; OR, odds ratio.

Received March 20, 2008.

Accepted June 23, 2008.

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