Associations of Total and High-Molecular-Weight Adiponectin With All-Cause and Cardiovascular Mortality in Older Persons The Cardiovascular Health Study

1 Weill Cornell Medical College, New York, NY
Circulation (Impact Factor: 14.43). 11/2012; 126(25). DOI: 10.1161/CIRCULATIONAHA.112.135202
Source: PubMed


Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk).

Methods and results:
In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio=0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio=1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio=1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality.

Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults.

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    • "Paradoxically, recent epidemiological studies have reported that higher adiponectin concentration was associated with total mortality, and even cardiovascular mortality, especially in older adults [8] [19] [20]. The reason for this so-called " adiponectin paradox " is unclear because positive associations between adiponectin concentration and mortality have been reported in different populations [21] [22]. "
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    ABSTRACT: Background: The relationship between adiponectin concentration and mortality is unclear. We examined whether serum adiponectin concentration is associated with all-cause and cardiovascular mortality in elderly Asians. Methods: We analyzed the data for community-dwelling adults ≥65 years of age (439 men and 561 women) who were enrolled in the Korean Longitudinal Study on Health and Aging (KLoSHA) cohort in prospective manner. The baseline serum total and high molecular weight adiponectin were measured using an enzyme-linked immunosorbent assay. Using Cox regression, we determined the associations between serum adiponectin concentration and all-cause and cardiovascular mortality after adjusting for well-known cardiovascular risk factors. Results: Over a mean follow-up time of 6.2 years, 222 individuals died, and 52 deaths (23.4%) were by cardiovascular disease. After adjusting confounding factors, elevated baseline serum adiponectin concentration was independently associated with all-cause mortality (adjusted hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.17-1.64) and cardiovascular mortality (HR 1.50; 1.06-2.14). We evaluated the effect modification by baseline body mass index (BMI). High serum adiponectin and low BMI were synergistically associated with increased all-cause mortality (HR 6.25; 3.08-12.71) and cardiovascular mortality (HR 13.94; 1.82-106.58). Conclusions: Higher serum adiponectin concentration was associated with increased all-cause and cardiovascular mortality in community-dwelling elderly Asian population. Our data supported the recent theory so called "adiponectin paradox". This relationship was strengthened when combined with low BMI. We suggest that measurement of adiponectin concentration and BMI together could be an additional predictive marker of survival among elderly adults.
    Full-text · Article · Mar 2015 · International Journal of Cardiology
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    • "Despite the direct association between serum adiponectin and CV mortality is difficult to reconcile with the well-recognized role of adiponectin as an anti inflammatory, anti-atherogenic and insulin sensitizer factor [2,3] and with the previously reported association with reduced risk of CHD [6,7,27], the same counter intuitive finding has been recently described in individuals from the general population and several selected clinical setting [11–17,19–23]. In addition, high adiponectin levels have been reported to predict all-cause mortality in the general population and in patients with CV disease [18–21], as well as in elderly people with type 2 diabetes [44]. "
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    ABSTRACT: Background The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood.While high serum adiponectin is associated with increased CV mortality in the general population, no data are available in type 2 diabetes.We here investigated whether this counterintuitive association was observable also in diabetic patients and whether it was sex-specific.Methods Three prospective cohorts were analyzed: 1) Gargano Heart Study (GHS; 359 patients, 58 events/1,934 person-years; py); 2) Health Professional Follow-up Study (HPFS; 833 men, 146 events/10,024 py); 3) Nurses¿ Health Study (NHS; 902 women, 144 events/15,074 py).ResultsIn GHS serum adiponectin predicted CV mortality in men (hazard ratio, HR, and 95% CI per standard deviation, SD, increment¿=¿1.54, 1.19-2.01), but not women (HR¿=¿0.98, 0.48-2.01).Circulating adiponectin predicted CV mortality in men from HPFS (HR¿=¿1.44, 1.21-1.72), but not in women from NHS (HR¿=¿1.08, 0.86-1.35), used as replication samples. In a pooled analysis, HRs were 1.47 (1.27-1.70) in 1,075 men and 1.07 (0.86-1.33) in 1,019 women (p for HRs heterogeneity across sexes¿=¿0.018).Conclusions This is the first report showing that high circulating adiponectin predicts increased CV mortality in men, but not in women with type 2 diabetes. Further studies are necessary to unravel the mechanisms through which adiponectin influences CV mortality in a sex-specific manner.
    Full-text · Article · Sep 2014 · Cardiovascular Diabetology
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    • "HR: 1.12 (0.95–1.32) Per SD Moderate Li, 2012 [29] China 449 68 65.5 MACE group: 4.97 ± 3.91 No-MACE group: 4.85 ± 2.47 CHD 1.6 ACM CVM OR: 2.47 (0.86–7.06) d OR: 1.07 (0.30–3.83) d Unequal two groups High Lindberg, 2012 [30] Denmark 735 74 63 6.9 (5.0–10.2) STEMI 2.25 ACM CVM HR: 2.07 1.34–3.20 HR: 2.57 1.46–4.50 "
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    ABSTRACT: Background The overall quantitative estimate on the possible association of adiponectin concentrations with mortality in patients with cardiovascular diseases (CVD) has not been reported. Methods We performed a systematic review and meta-analysis of prospective studies to evaluate the overall quantitative estimates on the adiponectin levels for risk of mortality in patients with CVD. MEDLINE, EMBASE, CINAHL, and the Cochrane Library (up to Mar 22, 2014) were used to search for studies evaluating the effect of adiponectin levels on mortality in patients with CVD. Random-effect models were selected to estimate overall effect estimates. Results Data from 14063 CVD patients enrolled in 15 prospective cohort and 1 nested case control studies were collated. The meta-analyses showed strong positive association of adiponectin with all-cause (n = 14 studies, overall pooled effect estimate = 1.45 [95% CI, 1.17-1.79]) and cardiovascular (n = 11 studies, overall pooled effect estimate = 1.69 [1.35-2.10]) mortality, for the highest tertile of adiponectin levels versus the lowest tertile. Subgroup analyses show study characteristics (including effect estimate, mean age, study location, sample sizes, gender, durations of follow-up, types of primary event, and acute or chronic CVD) did not substantially influence these positive associations. Conclusions Our results showed that increased baseline plasma adiponectin levels are significantly associated with elevated risk of all-cause and cardiovascular mortality in subjects with CVD. These positive associations may have been amplified by adjustment for potential intermediates or residual confounding, and their basis requires further investigation.
    Full-text · Article · Sep 2014 · Metabolism
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