Circulating Adiponectin Levels Are Paradoxically Associated With Mortality Rate: A Systematic Review and Meta-Analysis

Recent studies have suggested that higher body mass index (BMI) is associated with improved prognosis in chronic heart failure (CHF). The adipocytokine adiponectin is inversely associated with BMI, and in healthy subjects, low adiponectin is a predictor of mortality. In a prospective study, we therefore evaluated the association between plasma adiponectin levels and mortality among patients with CHF. In 195 CHF patients (age 69.3+/-10.2 years, BMI 27.3+/-5.2 kg/m2, left ventricular ejection fraction 30+/-8.9%, mean+/-SD), plasma adiponectin and N-terminal pro brain natriuretic peptide (NT-proBNP) were measured at baseline. Adiponectin was positively associated with NT-proBNP (beta=0.47, P<0.001), and both biomarkers were negatively associated with BMI (beta=-0.43, P<0.001 for adiponectin and beta=-0.38, P<0.001 for NT-proBNP, respectively) During a median follow-up of 2.6 years, 46 (23.5%) of the patients died. After adjustment for clinical variables associated with CHF severity (age, systolic blood pressure, left ventricular ejection fraction <25%, duration of CHF, and creatinine clearance) and for NT-proBNP, the hazard ratio of mortality for values in the 2 upper tertiles relative to the lowest tertile of adiponectin was 3.23 (P=0.032). BMI predicted mortality independently of clinical parameters of CHF severity (hazard ratio=0.63, P=0.012), but this association became insignificant after additional adjustment for NT-proBNP (hazard ratio=0.74, P=0.13). A high adiponectin level was a predictor of mortality, independent of risk markers of CHF severity, presumably because of its role as a marker for wasting. BMI was also associated with mortality, but a part of this relation may be mediated by adiponectin and NT-proBNP levels.

We investigated the functional relationship between natriuretic peptides and adiponectin by performing both experimental and clinical studies. Natriuretic peptides are promising candidates for the treatment of congestive heart failure (CHF) because of their wide range of beneficial effects on the cardiovascular system. Adiponectin is a cytokine derived from adipose tissue with various cardiovascular-protective effects that has been reported to show a positive association with plasma brain natriuretic peptide (BNP) levels in patients with heart failure. The expression of adiponectin messenger ribonucleic acid (mRNA) and its secretion were examined after atrial natriuretic peptide (ANP) or BNP was added to primary cultures of human adipocytes in the presence or absence of HS142-1 (a functional type A guanylyl cyclase receptor antagonist). Changes of the plasma adiponectin level were determined in 30 patients with CHF who were randomized to receive intravenous ANP (0.025 microg/kg/min human ANP for 3 days, n = 15) or saline (n = 15). Both ANP and BNP dose-dependently enhanced the expression of adiponectin mRNA and its secretion, whereas such enhancement was inhibited by pre-treatment with HS142-1. The plasma adiponectin level was increased at 4 days after administration of human ANP compared with the baseline value (from 6.56 +/- 0.40 microg/ml to 7.34 +/- 0.47 microg/ml, p < 0.05), whereas there was no change of adiponectin in the saline group (from 6.53 +/- 0.57 microg/ml to 6.55 +/- 0.56 microg/ml). Natriuretic peptides enhance adiponectin production by human adipocytes in vitro and even in patients with CHF, which might have a beneficial effect on cardiomyocytes in patients receiving recombinant natriuretic peptide therapy for heart failure.

Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality. We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models. Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer-specific or all-cause mortality. Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.